CNS

 Author:
            Krause, Michael; Rouleau, Agnes; Stark, Holger; Luger, Peter; Garbarg, Monique; et al.
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), EN, 329, 4, 1996, 209-215
 Title:
            New Potent Azomethine Prodrugs of the Histamine H3-Receptor Agonist
            (R)-a-Methylhistamine Containing a Heteroarylphenyl Partial Structure
 Abstract:
            The therapeutic value of histamine H3-receptor ligands is under current investigation.On
            the basis of recently described diaryl imine prodrugs of the histamine H3-receptor
            agonist (R)-a-methylhistamine (1) a series of new azomethine prodrugs containing five-
            and six-membered heterocycles were synthesized and tested for their in vitro hydrolysis
            rates and in vivo activity after oral application.It was found that electron-deficient
            six-membered heterocycles drastically destabilized the imine double bond so that these
            prodrugs decomposed unsuitably fast.On the contrary, prodrugs containing
            five-membered heterocycles appeared to be highly effective for the CNS delivery of 1,
            and a remarkable correlation between chemical structure and pharmacokinetic profile
            was observed.Particularly
            (R)-4-fluoro-2-<<N-<1-(1H-imidazol-4-yl)-2-propyl>imino>(1H-pyrrol-2-yl)methyl>phenol
            (8c), the 2-furanyl analogue 8d, and its 3-furanyl isomer 8e proved to be equipotent to
            the most potent of recently described halogenated diaryl imine prodrugs of 1.However,
            in contrast to any other azomethine prodrug, 8c exhibited an incomparably long lasting
            delivery of 1 in the CNS and can thus be regarded as a 'retard' prodrug.Assuming that a
            therapeutic indication of histamine H3-receptor agonists will soon be established, these
            highly potent heteroarylphenyl azomethine prodrugs, which already serve as valuable
            pharmacological tools, may also become potential drugs in clinical use. - Keywords:
            agonist; azomethine; histamine H3-receptor; prodrug
 CNR:
            6003869

 Author:
            Begley, David J.
 Reference:
            Journal, JPPMAB, J.Pharm.Pharmacol., EN, 48, 2, 1996, 136-146
 Title:
            The Blood-brain Barrier: Principles for Targeting Peptides and Drugs
            to the Central Nervous System
 Abstract:
            The presence of the blood-brain barrier (BBB), reduces the brain
            uptake of many drugs, peptides and other solutes from
            blood.Strategies for increasing the uptake of drugs and peptide-based
            drugs include; structural modifications to increase plasma half-life;
            improving passive penetration of the BBB by increasing the
            lipophilicity of the molecule; designing drugs which react with
            transporters present in the BBB; and reducing turnover and efflux from
            the central nervous system (CNS).
 CNR:
            6004862

 Author:
            Boksa, J.; Klodzinska, Aleksandra; Charakchieva-Minol, Sijka;
            Chojnacka-Wojcik, Ewa; Mokrosz, J. L.
 Reference:
            Journal, PHARAT, Pharmazie, EN, 51, 2, 1996, 72-76
 Title:
            Structure-activity relationship studies of CNS agents, Part 24: New analogs of
            N-tert.-butyl-3-<4-(2-methoxyphenyl)-1-piperazinyl>-2-phenylpropanamide
            (WAY-100135)
 Abstract:
            A series of new N-substituted derivatives of
            3-<4-(2-methoxyphenyl)-1-piperazinyl>-2-phenylpropanamide, 6-10, were
            synthesized and their 5-HT1A, 5-HT2A, and a1 receptor affinities were
            determined.All the compounds were highly potent 5-HT1A ligands with a
            moderate or low 5-HT2A and a1 affinity.It was shown that the 5-HT2A
            affinity of 1 and 6-10 depended crucially on the volume of amide
            substituents.None of the investigated racemic mixtures 1 and 6-8
            antagonized the 8-OH-DPAT-induced lower lip retraction in rats, whereas
            (+/-)-7 behaved like a weak agonist of 5-HT1A receptors in the model used.
 CNR:
            5996903

 Author:
            Krause, Michael; Rouleau, Agnes; Stark, Holger; Luger, Peter; Lipp, Ralph; et al.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 38, 20, 1995, 4070-4079
 Title:
            Synthesis, X-ray Crystallography, and Pharmacokinetics of Novel Azomethine Prodrugs of
            (R)-a-Methylhistamine: Highly Potent and Selective Histamine H3 Receptor Agonists
 Abstract:
            Since various neuroregulatory functions of the histamine H3 receptor have been proved
            during the last few years, the H3 receptor is of current interest.Azomethine derivatives of
            the highly potent histamine H3 receptor agonist (R)-a-methylhistamine (1) were prepared
            as lipophilic prodrugs to improve the bioavailability of the hydrophilic drug, particularly its
            entry into the brain.Additionally, azomethine derivatization provides protection against
            histamine methyltransferase, the major metabolizing enzyme in man, and thus efficiently
            enhances the bioavailability of 1.The molecular conformations of
            (R)-2<<N-<1-(1H-imidazol-4-yl)-2-propyl>imino>phenylmethyl>phenol (9a) and
            (R)-4-fluoro-2-<<N-<1-(1H-imidazol-4-yl)-2-propyl>imino>-(4-chlorophenyl)methyl>phenol
            (9p) were determined by X-ray structure analysis.An intramolecular hydrogen bond which
            is essential for the stability of these azomethines was thereby confirmed.Moreover, the
            pharmacokinetic parameters of the prodrugs were investigated in vitro as well as in
            vivo.The halogenated azomethines have an effect following peroral administration in
            mice, and some of them seem to be highly potent for the central nervous system (CNS)
            delivery of 1.At present the most potent prodrug of 1 is
            (R)-4-chloro-2-<<N-<1-(1H-imidazol-4-yl)-2-propyl>imino>(4-chlorophenyl)methyl>phenol
            (9q), reaching by far the highest CNS level of 1 (cmax=71 ng/g).Prodrugs of this type are
            not only valuable pharmacological tools but may also become H3 histaminergic drugs for
            therapeutic use.
 CNR:
            6005105

 Author:
            Rigo, Benoit; Kolokouris, Antonios; Kolokouris, Nicolas
 Reference:
            Journal, JHTCAD, J.Heterocycl.Chem., EN, 32, 5, 1995, 1489-1492
 Title:
            Studies on Pyrrolidinones. Synthesis of some N-Fatty
            Acylpyroglutamic Acids
 Abstract:
            Starting from readily available pyroglutamic acid 1, some N-fatty
            acylpyroglutamic acids were synthesized and characterized by their
            spectral data.A preliminary pharmacological study showed that
            N-stearoylpyroglutamic acid 4c displays a CNS stimulating effect on
            mice.
 CNR:
            6008542

 Author:
            Mokrosz, Jerzy L.; Paluchowska, Maria H.; Klodzinska, Aleksandra;
            Charakchieva-Minol, Sijka; Chojnacka-Wojcik, Ewa
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), EN, 328, 11/12, 1995,
            770-774
 Title:
            Structure-Activity Relationship Studies of CNS Agents, Part 26.
            4-<2-(Cycloalkanecarboxamido)ethyl>-1-(2-methoxyphenyl)-piperazines:
            High-Affinity 5-HT1A Agonists
 Abstract:
            4-<2-(Cycloalkanecarboxamido)ethyl>-1-(2-methoxyphenyl)piperazines
            8a-c, 8e, and 8h were obtained by acylation of
            4-(2-aminoethyl)-1-(2-methoxyphenyl)piperazine, and their 5-HT1A,
            5-HT2A and a1 receptor affinities were determined.It was found that the
            terminal cycloalkane moiety strongly stabilizes both the 5-HT1A and
            5-HT2A receptor-ligand complexes.It was demonstrated that the most
            active 5-HT1A ligands 8e and 8h (Ki = 2.1 and 0.21 nM, respectively)
            behaved as potent agonists of these receptors, i.e. both derivatives
            mimicked 8-OH-DPAT in the lower lip retraction (LLR) model and the
            effect was susceptible to blockade by reasonable doses of the selective
            5-HT1A receptor antagonist (S)-WAY-100135. - Keywords: 5-HT1A
            receptor ligands; 1-(2-methoxyphenyl)piperazines; hydrophobic effects;
            5-HT1A receptor agonists; LLR induction
 CNR:
            6009509

 Author:
            Mokrosz, Maria J.; Strekowski, Lucjan; Kozak, Wei Xing; Duszynska,
            Beata; Bojarski, Andrzej J.; et al.
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), EN, 328, 9, 1995,
            659-666
 Title:
            Structure-Activity Relationship Studies of CNS Agents, Part 25.
            4,6-Di(heteroaryl)-2-(N-methylpiperazino)pyrimidines as New, Potent
            5-HT2A Receptor Ligands: A Verification of the Topographic Model
 Abstract:
            A series of new 4,6-di(heteroaryl)pyrimidines containing an
            N-methylpiperazino group (6-13) or an ethylenediamine chain (15-20)
            in position 2 were synthesized and their 5-HT1A and 5-HT2A receptor
            affinities were determined.It was shown that the substituent effects on
            the 5-HT2a affinity are additive and could be described
            quantitatively.In a behavioral model it was also demonstrated that 6-11
            are 5-HT2A receptor antagonists.The molecular modelling results
            suggested that the distances between the basic nitrogen atom and the
            two aromatic centers (d1 = 5.2-8.4 Angstroem, d2 = 5.7-8.5 Angstroem,
            and d3 = 4.6-7.3 Angstroem) define the molecular topography of the
            5-HT2A receptor antagonists under study. - Keywords:
            4,6-di(heteroaryl)-2-(N-methylpiperazino)pyrimidines, structure -
            5-HT2A affinity relationships, 5-HT2A receptor antagonists,
            topographic model of 5-HT2A receptors
 CNR:
            6009645

 Author:
            Tripathi, R. C.; Dua, P. R.; Srimal, R. C.; Saxena, Anil K.
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 34, 2, 1995, 116-119
 Title:
            Synthesis and SAR in 1-aryloxy-3-(4-arylpiperazin-1-yl)propanes
 Abstract:
            1-<2-(3-Methylindol-2-yl)phenoxy>-3-(4-arylpiperazin-1-yl)propanes (7-11),
            1-(3/4-acetamino/aminophenoxy)-3-(4-arylpiperazin-1-yl)propanes
            (12-32) have been synthesized and evaluated for their CNS, CVS and
            antiinflammatory activities.The compounds, in general, have shown no
            effect or depressant action in gross behaviour.The phenyl ring with
            3-acetamino amino substituents in the aryloxy and with
            3-methyl/chloro substituents in the phenyl ring of the arylpiperazine
            part contribute maximum for the hypotensive and CNS depressant
            activities.
 CNR:
            5998921

 Author:
            Mokrosz, Jerzy L.; Bojarski, Andrzej J.; Charakchieva-Minol, Sijka;
            Duszynska, Beata; Mokrosz, Maria, J.; Paluchowska, Maria H.
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), EN, 328, 7-8, 1995,
            604-608
 Title:
            Structure-Activity Relationship Studies of CNS Agents, Part 23:
            N-(3-Phenylpropyl)- and
            N-<(E)-Cinnamyl>-1,2,3,4-tetrahydroisoquinoline Mimic
            1-Phenylpiperazine at 5-HT1A Receptors
 Abstract:
            The 5-HT1A receptor affinities and ionization constants of a set of
            1-arylpiperazine (4) 1,2,3,4-tetrahydroisoqinoline (6), and -quinoline (7)
            containing N-(w-arylalkyl) or N-(E)-cinnamyl substituents as well as
            two morpholine derivatives (8a, 8b) were determined.It was shown that
            some tetrahydroisoquinoline (6c, 6d) and morpholine (8a) derivatives
            were 5-HT1A ligands equipotentto 1-phenylpiperazine (4a) and
            1,2,3,4,4a,5-hexahydropyrazino<1,2-a>indole (5).On the basis of
            molecular modelling studies it was also demonstrated that 6c, 6d and
            8a mimicked very well the reference structures of 4a and its rigid
            analog 5.Another, more complex 1,2,3,4-tetrahydroisoquinoline
            derivative 3, which served as a model compound to confirm the
            previously reported 5-HT1A binding mode of derivatives 1a-d and 2,
            had the highest 5-HT1A affinity (Ki = 6.7 +/- 0.5 nM) of all the
            investigated compounds. - Keywords: 5-HT1A receptor ligands,
            1-arylpiperazines, N-substituted 1,2,3,4-tetrahydroisoquinolines,
            molecular modelling
 CNR:
            6002197

 Author:
            Mokrosz, Jerzy L.; Duszynska, Beata; Paluchowska, Maria H.;
            Charakchieva-Minol, S.; Mokrosz, Maria J.
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), EN, 328, 7-8, 1995,
            623-625
 Title:
            Structure-Activity Relationship Studies of CNS Agents, Part 22: A
            Search for New Trazodone-Like Antidepressants: Synthesis and
            Preliminary Receptor Binding Studies
 Abstract:
            New 1-phenyl- and 1-(3-chlorophenyl)piperazines containing a
            4-<3-heterocyclic)propyl> fragment were synthesized.It was found that
            of all the investigated compounds 11b (Ki = 13 +/- 2 nM) and 8b (Ki =
            38 +/- 2 nM) were the most active 5-HT1A and 5-HT2A ligands,
            respectively.Several derivatives (3a, 4a, 8b, 11b 12b, 13a, and 13b)
            were selected as good candidates for new, potential antidepressants
            on the basis of their 5-HT1A/5-HT2A receptor binding profiles. -
            Keywords: 1-arylpiperazines, trazodone analogs, 5-HT1A/5-HT2A
            binding profile
 CNR:
            6002201

 Author:
            Wallrauch, C.; Voss, A.; Milatovic, D.; Braveny, I.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., GE, 45, 6, 1995, 723-725
 Title:
            In-vitro-Aktivitaet von Sparfloxacin gegen Methicillin-resistente
            Staphylokokken
 Abstract:
            In vitro Activity of Sparfloxacin against Methicillin-resistant
            Staphylococci.The antimicrobial activity of sparfloxacin (CAS
            110871-86-8) against 154 clinical isolates of methicillin-resistant
            staphylococci was investigated and compared with that of 6 other
            fluoroquinolones.The isolates consisted of 100 methicillin-resistant
            Staphylococcus aureus (MRSA), 29 Staphylococcus epidermidis
            (MRSE) and 25 other coagulase-negative staphylococci
            (CNS).Sparfloxacin was more active than ciprofloxacin and the other
            fluoroquinolones against all strains tested.The MIC90 of sparfloxacin
            against the 100 isolates of Staphylococcus aureus was 8 mg/l, while
            that of ciprofloxacin was >/= 64 mg/l.Moreover,
            ciprofloxacin-susceptible MRSA isolates were inhibited by sparfloxacin
            at a concentration of </= 0.06 mg/l.The other quinolones had an MIC90
            ranging from 0.5 mg/l to 4 mg/l against ciprofloxacin-susceptible
            MRSA.Similar results were obtained for the MRSE and CNS isolates
            tested.As many as 90 percent of the ciprofloxacin-susceptible
            microorganisms were inhibited at a concentration of </= 0.06 mg/l or
            0.125 mg/l of sparfloxacin.The MIC90 of sparfloxacin against
            ciprofloxacin-resistant CNS and MRSE were 4 mg/l and 8 mg/l,
            respectively.Sparfloxacin was clearly more active than any of the other
            quinolones against all species tested, although higher concentrations
            were nedded to inhibit ciprofloxacin-resistant staphylococci. - Key
            words: Antibacterials Fluoroquinolones Sparfloxacin Staphylococci,
            methicillin-resistant
 CNR:
            5965574

 Author:
            Mokrosz, Jerzy L.; Klodzinska, Aleksandra; Boksa, Jan; Bojarski,
            Andrzej J.; Duszynska, Beata; Chojnacka-Wojcik, Ewa
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), EN, 328, 4, 1995,
            381-384
 Title:
            Structure-Activity Relationship Studies of CNS Agents, XXI: Two
            Derivatives of 1-(o-Methoxyphenyl)piperazine with an Opposite
            Function at 5-HT1A Receptors
 Abstract:
 CNR:
            5968888

 Author:
            Bridson, John N.; Schriver, Melbourne J.; Zhu, Shuguang
 Reference:
            Journal, CJCHAG, Can.J.Chem., EN, 73, 2, 1995, 212-222
 Title:
            Adamantane-based nitrile sulfides: the generation of the synthetic
            equivalent of the first bis(nitrile sulfide)
 Abstract:
            The reaction of 1,3-adamantanedicarbonamide with
            chlorocarbonylsulfenyl chloride in hot toluene gives two new
            oxathiazolone derivatives that have had their structures confirmed
            crystallographically: 1,3-bis(1,3,4-oxathiazol-2-on-5-yl)-adamantane
            and 1-cyano-3-(1,3,4-oxathiazol-2-on-5-yl)-adamantane. (Crystal data:
            C10H14(COC(O)SN)2: P21/m, a = 10.447(2), b = 7.119(3), c =
            10.684(2) Angstroem, b = 112.98(1) deg, V = 731.5(3) Angstroem3, z =
            2, Dc = 1.536 g cm-3, R = 0.034, Rw = 0.029;
            (NC)C10H14(COC(O)SN): P21/c, a = 9.153(2), b = 19.134(2), c =
            7.130(3) Angstroem, b = 105.38(2) deg, V = 1204(1) Angstroem3, z = 4,
            Dc = 1.447 g cm-3, R = 0.038, Rw = 0.035).The reaction of the precursor
            with dimethyl acetylenedicarboxylate (DMAD) in refluxing
            chlorobenzene gave a mixture that was resolved into pure compounds
            by Kugelrohr sublimation; these were shown to be sulfur, tetramethyl
            thiophenetetracarboxylate, 1,3-adamantanedinitrile,
            1,3-bis(4,5-bis(methoxycarbonyl)-isothiazol-3-yl)-adamantane, and
            1-cyano-3-(4,5-bis(methoxycarbonyl)-isothiazol-3-yl)-adamantane.The
            structures of the two new isothiazole derivatives were confirmed
            crystallographically. (Crystal data: C10H14(CNS*DMAD)2: Pca21, a =
            15.857(4), b = 11.562(4), c = 13.602(4) Angstroem, V = 2494(2)
            Angstroem3, z = 4, Dc = 1.424 g cm-3, R = 0.057, Rw = 0.038;
            C10H14(CN)(CNS*DMAD): P21/c, a = 19.683(2), b = 11.566(3), c =
            7.727(3) Angstroem, b = 93.30(2) deg, V = 1756(1) Angstroem3, z = 4,
            Dc = 1.363 g cm-3, R = 0.079, Rw = 0.076).The pattern of reactivity
            indicates that the synthetic equivalent of the bis(nitrile sulfide) may be
            present in solution but has a very short lifetime and failed to react at all
            with 1,3-adamantanedinitrile.Key words: oxathiazolone, nitrile sulfide,
            cycloaddition, isothiazole.
 CNR:
            5971788

 Author:
            Perregaard, Jens; Moltzen, Ejner K.; Meier, Eddi; Sanchez, Connie
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 38, 11, 1995, 1998-2008
 Title:
            s Ligands with Subnanomolar Affinity and Preference for the s2 Binding Site. 1.
            3-(w-Aminoalkyl)-1H-indoles
 Abstract:
            A series of 4-(1H-indol-3-yl)-1-butyl-substituted 4-phenylpiperidines,
            4-phenyl-1,2,3,6-tetrahydropyridines, and 4-phenylpiperazines was synthesized.The
            phenyl group was optionally substituted with 4-fluoro or 2-methoxy substituents.High
            affinity for both s1 and s2 binding sites was achieved with this compounds.Additionally,
            these compounds had relatively high affinity for serotonin 5-HT1A and 5-HT2A, dopamine
            D2, and adrenergic a1 receptors.Introduction of a 4-fluorophenyl substituent at the indole
            nitrogen atom rendered very selective s2 ligands with subnanomolar affinity for the s2
            binding site.The prototype of such a compound was
            1-(4-fluorophenyl)-3-<4-<4-(4-fluorophenyl)-1-piperidinyl>-1-butyl>-1H-indole, 11a (code
            no.Lu 29-253).This compound had the following binding affinities: IC50 (s1) = 16 nM, IC50
            (s2) = 0.27 nM, IC50 (5-HT1A) = 22 000 nM, IC50 (5-HT2A) = 270 nM, IC50 (D2) = 4200 nM,
            IC50 (a1) = 220 nM.Spiro-joining of the phenyl and the piperidine rings into a
            spiro<isobenzofuran-1(3H),4'-piperidine> ring system resulted in even more selective
            compounds.Variations of the 1-substituent at the indole and of the chain length of the
            alkylene spacer group were studied.The optimal compound was the spiro analogue of
            compound 11a.This compound is
            1'-<4-<1-(4-fluorophenyl)-1H-indol-3-yl>-1-butyl>spiro<isobenzofuran-1(3H),4'-piperidine>,
            14f (code no.Lu 28-179), with the binding affinities: IC50 (s1) = 17 nM, IC50 (s2) = 0.12 nM,
            IC50 (5-HT1A) = 21 000 nM, IC50 (5-HT2A) = 2000 nM, IC50 (D2) = 800 nM, IC50 (a1) =
            330 nM.However, the most selective s2 versus s1 ligand was the tropane derivative
            1-(4-fluorophenyl)-3-<4-<3-(4-fluorophenyl)-8-azabicyclo
            <3.2.1>oct-2-en-8-yl>-1-butyl>-1H-indole, 15a.This compound had the following binding
            affinities: IC50 (s1) = 1200 nM, IC50 (s2) = 2.5 nM.Potent anxiolytic activity in the
            black/white box exploration test in rats was found with the two most prominent s2 ligands
            Lu 29-253 and Lu 28-179.Good penetration into the CNS was documented both after
            subcutaneous and peroral administration of Lu 28-179 by ex vivo binding studies.Long
            duration of action was demonstrated both in ex vivo binding (T1/2 ca. 20 h) and in the
            black/white box exploration test.
 CNR:
            5973243

 Author:
            Giardina, Giuseppe; Clarke, Geoffrey D.; Grugni, Mario; Sbacchi,
            Massimo; Vecchietti, Vittorio
 Reference:
            Journal, FRMCE8, Farmaco, EN, 50, 6, 1995, 405-418
 Title:
            CENTRAL AND PERIPHERAL ANALGESIC AGENTS: CHEMICAL
            STRATEGIES FOR LIMITTING BRAIN PENETRATION IN
            KAPPA-OPIOID AGONISTS BELONGING TO DIFFERENT
            CHEMICAL CLASSES
 Abstract:
            Over the past decade there has been great interest by the
            pharmaceutical industry in the development of novel analgesics which
            act by activation of central k-opioid receptors.However, in view of the
            spectrum of unwanted CNS effects associated with such agents,
            recent efforts have been focused on peripherally-selective compounds
            with limited ability to cross the blood-brain barrier (BBB).In this review,
            the authors consider the chemical strategies and associated synthetic
            procedures employed by various research groups to produce
            hydrophilic compounds with retained k-opioid agonist
            activity.Physico-chemical (clogP, DlogP) and biological methods
            (antinociception following administration by peripheral and central
            routes; ex-vivo binding to detect plasma and brain levels of the drugs)
            utilized to assess brain penetration are described and
            compared.Overall, in-vivo ratios correlate better with DlogP values
            than with clogP.
 CNR:
            5974363

 Author:
            Wuensch, Bernhard; Zott, Matthias; Hoefner, Georg; Bauschke, Gerd
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), EN, 328, 6, 1995,
            487-496
 Title:
            Tricyclic CNS Active Agents by Intramolecular Oxa-Pictet-Spengler
            Reaction
 Abstract:
            Mitsunobu inversion of the (S)-configurated lactale (S)-7, which is
            prepared in four steps starting from (S)-tyrosine, leads to the
            (R)-configurated lactate (R)-7.The key step in the transformation of the
            enantiomeric lactates (S)-7 and (R)-7 into the benzomorphan
            analogous tricycles (R,S)-16a,b, (S,R)-16a,b, (S,S)-22, and (R,R)-22 is
            an intramolecular Oxa-Picted-Spengler reaction: The amides (S)-13,
            (R)-13, (S)-19 and (R)-19, in which the carbonyl moiety-masked as an
            acetal - is linked to the 2-phenylethanol moiety, are cyclized to give the
            tricyclic amides (R,S)-15, (S,R)-15, (S,S)-21 and (R,R)-21,
            respectively.In a concentration of 100 mM both enantiomers of 16a,
            16b, and 22 are not able to compete with 3H-(+)-MK 801 for the
            phencyclidine binding sites of NMDA receptors.In vivo, only (R,S)-16b
            and (S,S)-22 exhibit weak sedative and analgesic activity.
 CNR:
            5974589

 Author:
            Algate, D. R.; Augustin, J.; Atterson, P. R.; Beard, D. J.; Jobling, C. M.; et al.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 45, 2, 1995, 159-165
 Title:
            General Pharmacology of
            <2,2-Dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl>-acetic
            Acid in Experimental Animals
 Abstract:
            <2,2-Dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl>-acetic
            acid (ML 3000) is a newly synthesized compound with analgesic, antipyretic and
            anti-inflammatory activity.The general pharmacological effects of ML 3000
            following oral administration were investigated in experimental animals.The
            results showed that with regard to the CNS, ML 3000 did not affect behaviour in
            the Irwin test, locomotor activity or hexobarbital-induced sleep at doses of 30, 100
            and 300 mg/kg.ML 3000, at a single dose of 100 mg/kg administered
            intraduodenally, had no notable effect on the cardiovascular system or respiration
            in anaesthetised rats and dogs nor on neuromuscular function in anaesthetised
            cats.No evidence of gastric damage or disturbance of peristalsis was observed
            following oral administration of ML 3000.In vitro, ML 3000 evoked a weak
            spasmogenic response in the guinea-pig ileum with a dose-related inhibition of
            acetylcholine, histamine and barium chloride-induced responses.A small transient
            reduction in urine volume was observed after the highest dose accompanied by
            decreases in electrolyte excretion at doses of 100 and 300 mg/kg in rats.The
            results demonstrate that ML 3000 has no notable general pharmacological effects
            under the experimental conditions reported. - Key words: Anti-inflammatories,
            non-steroidal,
            <2,2-Dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl>-acetic
            acid, ML 3000, general pharmacology
 CNR:
            5942566

 Author:
            Mokrosz, Jerzy L.; Mokrosz, Maria J.; Charakchieva-Minol, Sijka;
            Paluchowska, Maria H.; Bojarski, Andrzej J.; Duszynska, Beata
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), EN, 328, 2, 1995,
            143-148
 Title:
            Structure-Activity Relationship Studies of CNS Agents, XIX:
            Quantitative Analysis of the Alkyl Chain Effects on the 5-HT1A and
            5-HT2 Receptor Affinities of 4-Alkyl-1-arylpiperazines and Their
            Analogs
 Abstract:
            The 5-HT1A and 5-HT2 receptor affinity of a set of 44 N-alkylated
            1-arylpiperazines and their analogs has been analyzed: the n-hexyl
            derivatives were the most potent and the most selective 5-HT1A
            ligands of all the investigated N-alkyl homologues.The alkyl chain may
            stabilize the 5-HT1A receptor-ligand complex by hydrophobic forces.A
            set of the alkyl substituent contributions (CHT1A) for prediction of the
            5-HT1A affinity of N-alkyl derivatives of 1-arylpiperazines and related
            compounds have been defined on the basis of the Free-Wilson
            analysis.
 CNR:
            5944394

 Author:
            Vega, S.; Gil, M. Soledad; Darias, V.; Mateo, Candelaria C. Sanchez; Exposito, Maria
            A.
 Reference:
            Journal, PHARAT, Pharmazie, EN, 50, 1, 1995, 27-33
 Title:
            Synthesis and pharmacological study of
            5,6,8,9-tetrahydro-4H,7H-pyrrolo<1,2-a>cyclopenta<b>thieno<3,2-f><1,4>diazepines
 Abstract:
            The paper reports the synthesis of a series of
            5,6,8,9-tetrahydro-4H,7H-pyrrolo<1,2-a>cyclopenta<b>thieno<3,2-f><1,4>diazepines
            and the results of the study on their CNS activity in mice.The pharmacological
            properties of a previously prepared series of 5,6,7,8,9,10-hexahydro-benzo-analogs
            is also described.
 CNR:
            5944544

 Author:
            Knabe, Joachim; Buech, Horst Paul; Bender, Susanne
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), GE, 328, 1, 1995,
            59-66
 Title:
            1,5-Benzodiazepines, II: Diametrically Opposite CNS-Effects Between
            the Enantiomers of two 3,3-Dialkyl-1,5-benzodiazepine-2,4-diones
 Abstract:
            I.p. applicated S(+)-1, R(-)-1 and rac. 1 prolonged hexobarbital
            sleeping in rats.The rac. 8-chloro compound 3 given i.p. produced no
            prolongation.Determination of rac. 1 in serum and tissues of rats 30
            min after i.p. administration of 50 mg/kg showed that rac. 1 was
            detectable in serum and brain, yet its concentration was below the limit
            of determination.I.v. applicated, the enantiomers of 1 and 3 showed
            diametrically opposite CNS-effects: The S(+)-enantiomers were
            convulsively active as pentetrazol, whereas the R(-)-enantiomers were
            CNS depressant active prolonging hexobarbital sleeping time
            dose-dependently.High doses of diazepam antagonized dose
            dependently the convulsive action of S(+)-1 supporting the hypothesis
            that this enantiomer acted as a strong inverse agonist, whereas R(-)-1
            produced weak agonistic activity at the benzodiazepine binding site of
            the GABA-receptor. - Enantioselective differences for the binding of the
            1-enantiomers to human serum albumin were found, too.R(-)-1 was
            bound to a greater extent than S(+)-1.
 CNR:
            5944743

 Author:
            Flagmeyer, I.; Gebert, I.; Staay, F. J. van der
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 45, 4, 1995, 456-459
 Title:
            General Pharmacology of the Putative Cognition Enhancer Linopirdine
 Abstract:
            The putative cognition enhancer linopirdine
            (3,3-bis(4-pyridinylmethyl)-1-phenylindolin-2-one, CAS 105431-72-9)
            is supposed to act by enhancing the release of neurotransmitters,
            especially acetylcholine.The present study assessed the effects of a
            single administration of this compound on the central nervous system
            in eight different rat and mouse models (CNS general
            pharmacology).In each test performed, linopirdine was administered
            subcutaneously in doses of 3, 10, and 30 mg/kg.The compound did not
            affect traction ability and nociceptive responsiveness nor did it induce
            catalepsy.Linopirdine impaired motor coordination in the balance r od
            test.The compound showed a distinct proconvulsive action in the
            pentylenetetrazole threshold dose test and induced in the highest dose
            tested (30 mg/kg) lethal seizures in some mice.It increased the
            duration of hexobarbital-induced anaesthesia in mice.Rats treated with
            linopirdine showed ptosis, salivation, slight sedation, paw beating and
            slight hypothermia.These results support the hypothesis that
            linopirdine acts by elevating the release of different neutrotransmitters
            such as acetylcholine and dopamine.The compound has a low
            potential to produce side effects at pharmacodynamic active doses. -
            Key words:CAS 105431-72-9; Cognition enhancer; Linopirdine,
            pharmacology
 CNR:
            5952508

 Author:
            Kreutzberg, G. W.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 45, 3, 1995, 357-360
 Title:
            Microglia, the First Line of Defence in Brain Pathologies
 Abstract:
            Microglial cells account for approximately 20percent of the total glial
            population in the central nervous system.They are distributed with no
            significant local differences in the white and grey matters.In contrast to
            astrocytes they cover non-overlapping territories.They belong to the
            mononuclear phagocyte system and form the resident macrophages in
            the brain tissue, the spinal cord and the retina.Their function in the
            normal neural parenchyma is unknown.However, in various
            pathologies they form a most reactive sensor to threats to the nervous
            system.Within a few hours they exhibit an activation program that we
            have studied in seven different experimental paradigms, e.g. following
            nerve section, direct brain trauma, toxic lesion, spreading depression,
            ischemic lesion, fiber degeneration, autoimmune diseases.Activated
            microglial cells become immuno-competent and are MHC (major
            histocompatibility complex) class 1 and class 2 positive.They express
            the amyloid precursor protein, APP.The complement receptor CR3bi is
            quickly upregulated.The mitotic activity depends on the colony
            stimulating factor.M-CSF and GM-CSF and the appropriate
            receptors.Molecules discussed as signals in the activation process of
            microglia are cytokines such as IL-1, IL-2, IL-6, TGFb1.An important
            role could also be attributed to the unique potassium channel of
            microglia.Brain macrophages of microglial origin have a strong
            respiratory burst activity, meaning that they produce oxygen
            radicals.They also possess Cathepsin B and L and thus are potentially
            cytotoxic.Taken together, microglia are highly reactive, mobile and
            multifunctional immune cells of the CNS that can play a universal role
            in the defence of the neural parenchyma.Key words: b-Amyloid
            precursor protein; Brain pathologies, defence systems; Complement;
            Microglial cells, role in neuropathologies
 CNR:
            5953888

 Author:
            Evangelista, S.; Ballati, L.; Boni, P.; Castellucci, A.; Perretti, F.; et al.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 45, 5, 1995, 569-575
 Title:
            Pharmacodynamic Profile of the New Potent Antibronchospastic Agent
            7-<(2,2-Dimethyl)propyl>-1-methyl Xanthine
 Abstract:
            The pharmacodynamic profile of a new xanthine derivative,
            7-<(2,2-dimethyl)propyl>-1-methyl xanthine (CAS 155006-67-0,
            MX2/120), was investigated in comparison with theophylline.The
            compound reduces in vitro the bronchospastic tone induced by
            carbachol or histamine in guinea-pig bronchi, with a potency 11 and 5
            fold greater than theophylline, respectively.MX2/120 is significantly
            more active and long-lasting than theophylline in in vivo experiments
            toward spasmogens such as acetylcholine (ED50 over 5 h=15 mmol/kg
            p.o. vs 230 mmol/kg p.o.) or histamine (ED50 over 5 h=122 mmol/kg p.o.
            vs 500 mmol/kg p.o.) while being almost equiactive to theophylline
            toward antigen and capsaicin induced cough strokes.MX2/120, if
            administered by i.p. route reduces hyper-responsiveness to histamine
            induced by PAF and extravasation of protein into bronchoalveolar
            lavage fluid induced by capsaicin.These anti-inflammatory effects of
            MX2/120 are of similar extent when compared to theophylline.Unlike
            theophylline, MX2/120 up to 275 mmol/kg p.o. possesses little or no
            CNS excitatory effects in mice in terms of reduction of sleeping time
            induced by chlodiazepoxide, increase in mortality and convulsions
            induced by pentetrazol and increase in locomotor activity.This reduced
            neuroexcitatory action is probably related to its lack of affinity to
            adenosine receptors that could also explain the absence of effect on
            basal gastric secretion.Chronotropic effects of MX2/120 in conscious
            rats are similar to those of theophylline while the effects of both drugs
            on blood pressure are of minor extent.The overall pharmacodynamic
            properties of MX2/120 are superior to those of theophylline in relation
            to its antibronchospastic activity and lack of excitatory effects on CNS.
            -Key words: Antiasthmatics; CAS 155006-67-0;
            7-<(2,2-Dimethyl)propyl>-1-methyl xanthine; MX2/120,
            pharmacodynamics; Theophylline
 CNR:
            5954108

 Author:
            Harris, Wayne T.; Tenjarla, Srinivas N.; Holbrook, John M.; Smith,
            Jeffrey; Mead, Cecelia; Entrekin, Joseph
 Reference:
            Journal, JPMSAE, J.Pharm.Sci., EN, 84, 5, 1995, 640-642
 Title:
            N-Pentyl N-Acetylprolinate. A New Skin Penetration Enhancer
 Abstract:
            The activity of n-pentyl N-acetylprolinate (PNAP) as a transdermal
            penetration enhancer was investigated.PNAP was synthesized from
            L-proline by acetylation with acetic anhydride, followed by
            acid-catalyzed esterification with 1-pentanol.Structure confirmation
            was accomplished by IR and NMR spectroscopy and elemental
            analysis.Benzoic acid (BA) was used as a model drug, and the effect of
            PNAP on the flux of BA through human cadaver skin was
            evaluated.The central nervous system (CNS) toxicity of PNAP was
            evaluated by comparing the effects of intraperitoneal administration of
            PNAP to mice with those of laurocapram (Azone), a known penetration
            enhancer.Based on preliminary studies, PNAP appears to be an
            effective transdermal penetration enhancer, is nontoxic at low doses,
            and exhibits dose-related CNS toxicity at higher doses.
 CNR:
            5956145

 Author:
            Malinka, Wieslaw; Sieklucka-Dziuba, Maria; Rajtar-Cynke, Grazyna;
            Gasior, Maciej; Kleinrok, Zdsislaw
 Reference:
            Journal, FRMCE8, Farmaco, EN, 50, 1, 1995, 29-36
 Title:
            SYNTHESIS AND PHARMACOLOGICAL STUDY OF SOME
            DERIVATIVES OF
            PYRAZOLO<4,3-c>PYRIDO<3,2-e>-1,2-THIAZINE-5,5-DIOXIDE, A
            NOVEL HETEROCYCLIC RING SYSTEM
 Abstract:
            Starting from pyridothiazines 1 and N-methyl(phenyl)hydrazines
            isomeric derivatives 2 and 3 of the
            pyrazolo<4,3-c>pyrido<3,2-e>-1,2-thiazine, a new heterocyclic ring
            system, have been obtained.The structure of the synthesized
            compounds was confirmed by spectroscopic and elemental
            analyses.The results of the preliminary pharmacological study of CNS
            effects caused by compounds 2 are reported.
 CNR:
            5956193

 Author:
            Boksa, J.; Duszynska, Beata; Mokrosz, J. L.
 Reference:
            Journal, PHARAT, Pharmazie, EN, 50, 3, 1995, 220-221
 Title:
            Structure-activity relationship studies of CNS agents, part 20:
            9-<w-<1-(m-Chlorophenyl)-4-piperazinyl>alkyl>-1,2,3,4-tetrahydro-b-carbolines:
            New 5-HT1A and 5-HT2A receptor ligands
 Abstract:
 CNR:
            5956734

 Author:
            Zawadowski, Teodor; Kossakowski, Jerzy; Rump, Slawomir; Jakowicz, Izabella; Plaznik, Adam
 Reference:
            Journal, APPHAX, Acta Pol.Pharm., EN, 52, 1, 1995, 43-46
 Title:
            SYNTHESIS AND ANXIOLYTIC ACTIVITY OF N-SUBSTITUTED CYCLIC IMIDES
            N-<4-<(4-ARYL)-1-PIPERAZINYL>ALKYL>-5,7-DIOXABICYCLO<2.2.2>OCTANE-2,3-DICARBOXIMIDE
 Abstract:
            The preparation of N-substituted cyclic imides
            N-<4-<(4-aryl)-1-piperazinyl>alkyl>-5,7-dioxabicyclo<2.2.2>octane-2,3-dicarboximides by condensation
            of N-(3-chloropropyl)- or N-(4-chlorobutyl)imides with appropriate amine has been described.One of
            compounds was tested in the Vogel's test and displayed an expected activity on CNS.
            6,7-dioxabicyclo<2.2.2>octane-2,3-dicarboxylic acid derivatives, synthesis, anxiolytic activity
 CNR:
            5958786

 Author:
            Sarro, A. de; Imperatore, C.; Mastroeni, P.; Sarro, G. de
 Reference:
            Journal, JPPMAB, J.Pharm.Pharmacol., EN, 47, 4, 1995, 292-296
 Title:
            Comparative Convulsant Potencies of Two Carbapenem Derivatives
            in C57 and DBA/2 Mice
 Abstract:
            The behavioural and convulsant effects of imipenem and meropenem
            were studied after intraperitoneal administration in DBA/2 mice, a
            strain genetically susceptible to sound-induced seizure, and in C57
            mice, a strain not prone to seizure.DBA/2 mice were more susceptible
            than C57 mice to seizures induced by imipenem-cilastatin or
            meropenem.Imipenem was also 1.9 times more potent than
            meropenem in inducing clonus in DBA/2 mice.To investigate the
            possibility that the seizure-inducing activity of imipenem might be due
            to a probenecid-like effect of cilastatin, animals were treated with
            imipenem alone.No significant differences were observed between
            imipenem-cilastatin and imipenem-treated animals.Thus, it is
            reasonable to exclude a probenecid-like effect of cilastatin.Although
            the main mechanism for seizure-like activity of imipenem cannot be
            easily determined, we believe that several mechanisms may be
            involved.An increased excitation of the central nervous system (CNS)
            by inhibition of GABA binding to receptors and a slow clearance of
            imipenem from the CNS may be postulated.Cilastatin did not induce
            seizures.In addition, meropenem, a compound structurally related to
            imipenem, showed weak or no convulsant effects.
 CNR:
            5960664

 Author:
            Portoghese, P. S.; Farouz-Grant, F.; Sultana, M.; Takemori, A. E.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 38, 3, 1995, 402-407
 Title:
            7'-Substituted Amino Acid Conjugates of Naltrindole. Hydrophilic
            Groups as Determinants of Selective Antagonism of d1 Opioid
            Receptor-Mediated Antinociception in Mice
 Abstract:
            A series of amino acid conjugates (2-6) of naltrindole (1) were
            synthesized from 7'-carboxynaltrindole (7) in order to obtain s
            antagonists that would have minimal access to the central nervous
            system (CNS) upon peripheral administration.All of the ligands (2-7)
            were tested in smooth muscle preparations and found to be potent and
            selective s opioid antagonists.Receptor binding showed 2-7 to be
            highly s-selective, with Ki ratios (m/d, k/d) ranging from 127 to 38
            000.Two of the more selective conjugates, the glycinate 2 and
            aspartate 3, were evaluated by the iv and icv routes in mice, and they
            afforded very high iv/icv dose ratios (112 766 and 46 667, respectively)
            consistent with poor CNS penetration.The in vivo testing revealed that
            2 and 3 are d1-selective antagonists, in contrast to naltriben and related
            ligands which are d2-selective.The fact that the binding data are not
            consistent with the in vivo data suggests that the origin of the selectivity
            of naltrindole congeners may be related to selective access to tissue
            compartments in the CNS rather than to binding affinity differences
            between d opioid receptor subtypes.
 CNR:
            5960850

 Author:
            Dauzonne, D.; Gillardin, J. M.; Lepage, F.; Pointet, R.; Risse, S.; et al.
 Reference:
            Journal, EJMCA5, Eur.J.Med.Chem.Chim.Ther., EN, 30, 1, 1995,
            53-60
 Title:
            Synthesis and some CNS activities of new
            benzofuranylacryloylpiperazines
 Abstract:
            A series of novel benzofuranylacryloylpiperazines, which are
            structurally related to both cinnamamide derivatives and befuraline,
            have been prepared as their hydrochlorides.Their anticonvulsant and
            antidepressant activities against seizures induced by electroshock and
            against tetrabenazine-induced palpebral ptosis have been evaluated in
            mice.Some of them revealed interesting potencies since, although
            they are less active than the reference drugs, they exhibited a higher
            protective index. CNS / benzofuran / chromene / piperazine / vinilogy /
            anticonvulsant activity / antidepressant activity
 CNR:
            5960923

 Author:
            Iwasaki, Nobuhiko; Ohashi, Tetsuo; Musoh, Keiichi; Nishino, Hiroyuki; Kado, Noriyuki; et al.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 38, 3, 1995, 496-507
 Title:
            Amphoteric Drugs. 3. Synthesis and Antiallergic Activity of
            3-<(5,11-Dihydro<1>benzoxepino<4,3-b>pyridin-11-ylidene)piperidino>propionic Acid
            Derivatives and Related Compounds
 Abstract:
            An important approach to the design of antiallergic agents with reduced penetration into the
            central nervous system (CNS) is described.A series of
            3-<(5,11-dihydro<1>benzoxepino<4,3-b>pyridin-11-ylidene)piperidino>propionic acid
            derivatives (31-47) and related compounds (48-54) were synthesized and evaluated for
            antiallergic activity and penetration of a compound into the CNS in comparison with the
            corresponding 6H-dibenz<b,e>oxepin derivative (3).Combination of zwitterionization and
            introduction of a pyridine component resulted in an increase in antiallergic activity and a
            great reduction of penetration into the CNS, which was evaluated by the selectivity (B/A) of
            antihistaminic activities in the central system <ID50 value (B) for ex vivo H1 binding to
            mouse brain membranes> and in the peripheral system <ED50 value (A) for inhibitory effect
            on histamine-induced increase in vascular permeability in mice>.This surprising reduction
            of penetration into the CNS could be considered on the basis of an increase in hydrophilicity
            caused by both of the zwitterionization and the introduction of a pyridine component.
            3-<4-(8-Fluoro-5,11-dihydro<1>benzoxepino<4,3-b>pyridin-11-ylidene)piperidino>propionic
            acid (33) exhibited a strong antiallergic effect in various experimental models and very low
            penetration into the CNS.Compound 33 (HSR-609) is now under clinical trial as a promising
            antiallergic agent with greatly reduced penetration into the CNS.
 CNR:
            5961325

 Author:
            Urban, Frank J.; Breitenbach, Ralph; Murtiashaw, Charles W.;
            Vanderplas, Brian C.
 Reference:
            Journal, TASYE3, Tetrahedron: Asymmetry, EN, 6, 2, 1995, 321-324
 Title:
            Synthesis of an Optically Active Octahydro-2H-pyrido<1,2-a>pyrazine
            Based CNS Agent
 Abstract:
            A synthesis of an optically active octahydro-2H-pyrido<1,2-a>pyrazine
            is presented.The key sequence involved the equilibration of an
            optically active cis-aldehyde to give the thermodynamic transaldehyde
            that was trapped by nitromethane anion.
 CNR:
            5962222

 Author:
            Tietze, Lutz F.; Burkhardt, Olaf
 Reference:
            Journal, LANAEM, Liebigs Ann.Org.Bioorg.Chem., EN, 7, 1995,
            1153-1158
 Title:
            Stereo- and Regioselective Intramolecular Heck Reaction of a-Amino
            Acid Derivatives for the Synthesis of Enantiopure
            3,4-Dihydroisoquinolinones
 Abstract:
            Acylation of the alkenes 1a-d and 3, easily prepared from the
            corresponding a-amino acids, with 2-iodobenzoyl chloride gives 2a-d
            and 4 which cyclize to the enantiopure dihydroisoquinolinones 5a-d
            and 9, resp., in an intramolecular Heck reaction using 5 mol-percent of
            Pd(OAc)2 in the presence of PPh3, TPAB, and KOAc with excellent
            diastereoselectivity. - Keywords: Heck reaction, intramolecular;
            a-Amino acids; Isoquinolinones; Palladium catalyst; Heterocycles;
            CNS agents
 CNR:
            5964219

 Author:
            Dunbar, Philip G.; Durant, Graham J.; Rho, Taikyun; Ojo, Babatunde;
            Huzl, James J.; et al.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 37, 17, 1994, 2774-2782
 Title:
            Design, Synthesis, and Neurochemical Evaluation of
            2-Amino-5-(alkoxycarbonyl)-3,4,5,6-tetrahydropyridines and
            2-Amino-5-(alkoxycarbonyl)-1,4,5,6-tetrahydropyrimidines as M1
            Muscarinic Receptor Agonists
 Abstract:
            Four regioisomers of
            2-amino-(methoxycarbonyl)-3,4,5,6-tetrahydropyridine (2a-5a) were
            synthesized as the racemates to evaluate the utility of exocyclic
            amidines in the development of novel agonists for M1 muscarinic
            receptors.Of the four regioisomers, only racemic
            2-amino-5-(methoxycarbonyl)-3,4,5,6-tetrahydropyridine (4a,
            CDD-OO75-A) displayed high affinity (IC50 = 10 +/- 3.0 mM) and
            activity at muscarinic receptors coupled to PI metabolism in the rat
            cortex (260 +/- 4.5percent stimulation above basal levels at 100 mM).A
            series of 2-amino-5-(alkoxycarbonyl)-3,4,5,6-tetrahydropyridines then
            was synthesized for further evaluation as M1 agonists.Only the
            propargyl derivative (4d) retained substantial agonist activity (120 +/-
            14percent at 100 mM) in this series.On the basis of the activity of the
            5-(alkoxycarbonyl)-1,4,5,6-tetrahydropyrimidines (1a and 1d) and the
            2-amino-5-(alkoxycarbonyl)-3,4,5,6-tetrahydropyridines, the
            corresponding cyclic guainidine derivatives were synthesized and
            tested. 2-Amino-5-(methoxycarbonyl)-1,4,5,6- tetrahydropyrimidine
            (7a) displayed a modest affinity for muscarinic receptors in the CNS
            (22 +/- 5.3 mM) and an ability to stimulate PI turnover in rat cerebral
            cortex (81 +/- 16percent at 100 mM).The propargyl derivative (7d) also
            had modest binding affinity (31 +/- 15 mM) and high activity (150 +/- 8.5
            at 100 mM), as expected based on the activity of propargyl esters of
            1,4,5,6-tetrahydropyrimidine and
            2-amino-3,4,5,6-tetrahydropyridine.Computational chemical studies
            revealed five distinct minimum energy conformations for 1a, (R)-4a
            and 7a, and three for 1d, (R)-4d, and 7d, each with unique orientation
            of the ester moiety.Each of the five conformations for 1a could be
            superimposed upon a unique conformer of (R)-4a and 7a, suggesting
            that the compounds interact with muscarinic receptors in a similar
            fashion.Taken together, the data indicate the general utility of amidine
            systems as suitable replacements for the ammonium group of
            acetylcholine in developing ligands with activity at M1 muscarinic
            receptors in the central nervous system.Such compounds might be
            useful in the treatment of patients with Alzheimer's disease.
 CNR:
            5970384

 Author:
            Wuensch, Bernhard; Diekmann, Heike
 Reference:
            Journal, HTCYAM, Heterocycles, EN, 38, 4, 1994, 709-712
 Title:
            CNS AGENTS: OPTICAL RESOLUTION WITH BAKER'S YEAST AS
            KEY STEP IN THE SYNTHESIS OF OPTICALLY ACTIVE TRICYCLIC
            AMINES
 Abstract:
            The synthesis of the optically active
            1,5-epoxy-3,4,5,6-tetrahydro-N-methyl-1H-2-benzoxocin-6-amines
            ((-)-10) and ((+)-10) is achieved by optical resolution of the racemic
            1,5-epoxy-4,5-dihydro-1H-2-benzoxocin-6(3H)-one ((+/-)-8) with
            baker's yeast as the key step. (+)-10 can also be prepared starting with
            the homochiral a-hydroxy-g-butyrolactone ((-)-6a), which is easily
            obtained from (S)-(-)-malic acid.
 CNR:
            5972723

 Author:
            Carceller, Elena; Merlos, Manuel; Giral, Marta; Balsa, Dolors; Almansa,
            Carmen; et al.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 37, 17, 1994, 2697-2703
 Title:
            <(3-Pyridylalkyl)piperidylidene>benzocycloheptapyridine Derivatives
            as Dual Antagonists of PAF and Histamine
 Abstract:
            A series of <(3-pyridylalkyl)piperidylidene>- and
            (nicotinoylpiperidylidene)benzocycloheptapyridine derivatives, Ia,b,
            were prepared and evaluated for PAF antagonist and H1 antihistamine
            activity.PAF antagonist activity was investigated by the in vitro
            PAF-induced platelet aggregation assay (PPA) and the in vivo
            PAF-induced hypotension test in rats (PH) and mortality test in mice
            (PM).For the evaluation of H1 antihistamine activity, the in vitro
            histamine-induced contraction of the guinea-pig ileum assay (HC) and
            the in vivo histamine-induced hypotension test (HH) in normotensive
            rats were used.The potential antiallergic activity of the compounds was
            evaluated using the active anaphylactic shock test in mice.These
            compounds are structurally related to loratadine (1) and were
            generated by replacement of the ethoxycarbonyl group of 1 with
            substituted 3-pyridylmethyl and nicotinoyl moieties. Both anti-PAF and
            H1 antihistamine activities have shown a high dependence on the
            exact nature and position of the substituent in the pyridine
            ring.Optimum structure 19 (UR-12592) incorporating a
            (5-methyl-3-pyridyl)methyl radical displayed an unique dual activity
            inhibiting both PAF-induced effects (PPA, IC50 = 3.7 mM; PH, ID50 =
            0.44 mg/kg iv; PM, ID50 = 1.9 mg/kg po) and histamine-induced effects
            (HC, IC50 = 3.9 nM; HH, ID50 = 1.4 mg/kg iv).Furthermore, 19 was
            highly active in the passive cutaneous anaphylactic shock in rats (ID50
            = 1.2 mg/kg po) and strongly protected mice and rats from mortality
            induced by endotoxin (ID50 = 1.2 and 0.5 mg/kg iv,
            respectively).Compound 19 showed itself to be devoid of CNS
            depressant effects, neither modifying spontaneous motor activity nor
            prolonging barbiturate-sleeping time in mice at a dose of 100 mg/kg
            po, and is now under development.
 CNR:
            5973579

 Author:
            Francis, P. C.; Carlson, K. H.; Owen, N. V.; Adams, E. R.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 44, 3, 1994, 278-284
 Title:
            Preclinical Toxicology Studies with the New Dopamine Agonist
            Pergolide. Acute, subchronic, and chronic evaluations
 Abstract:
            Pergolide (LY127809, CAS 66104-23-2), a dopamine agonist for the
            treatment of Parkinson's disease, was evaluated for toxicity in acute,
            subchronic, and chronic studies.Acute toxicity tests using oral,
            intravenous and intraperitoneal routes were conducted in rats, mice,
            rabbits, and dogs.The acute oral medium lethal doses (MLD) ranged
            from 8.4 to 33.6 mg/kg in Wistar and Fischer 344 rats, and from 54.0 to
            87.2 mg/kg in ICR mice.Oral doses of 20 and 25 mg/kg produced no
            mortality in rabbits or dogs, respectively.The MLD by the iv route
            ranged from 0.59 to 0.87 mg/kg for Fischer 344 rats and from 11.6 to
            37.1 mg/kg for ICR mice.The predominant signs of toxicity in the acute
            studies included hyperactivity, poor grooming, ptosis, aggressive
            behavior, increased gnawing activity, tremors, convulsions, and
            emesis.In the subchronic and chronic studies, Fischer 344 rats,
            B6C3F1 mice, and beagle dogs were administered pergolide either by
            gavage or in the diet for up to 1 year.Daily doses in these studies
            ranged up to 20 mg/kg for rats, 45 mg/kg for mice, and 5 mg/kg for
            dogs.The predominant treatment-related effects seen in these studies
            were attributable to the pharmacologic activity of pergolide.These
            consisted primarily of CNS-mediated clinical signs in rats and dogs,
            weigth loss or decreased weight gain, emesis in dogs, and inhibition of
            lysis of corpora lutea with a corresponding increase in the weight of the
            uterus and ovaries.Pergolide treatment was not associated with any
            specific target organ toxicity.Decreased erythrocytic parameters and
            increased serum enzyme values seen in the repeated-dose studies
            were considered to be secondary responses to the effects on body
            weight.In the 1-year studies with rats and dogs, the
            no-observed-adverse-effect levels (NOAEL) were 0.06 and 0.1 mg/kg,
            respectively. - Key words: CAS 66104-23-2; Dopamine agonists;
            LY127809; Pergolide, toxicology studies; Permax
 CNR:
            5851248

 Author:
            Wyrick, Steven D.; Myers, Andrew M.; Booth, Raymond G.; Kula, Nora S.; Baldessarini,
            Ross J.; Mailman, Richard B.
 Reference:
            Journal, JLCRD4, J.Labelled Compd.Radiopharm., EN, 34, 2, 1994, 131-134
 Title:
            Synthesis of
            <N-C3H3>-trans-(1R,3S)-(-)-1-Phenyl-3-N,N-dimethylamino-1,2,3,4-tetrahydronaphthalene
            (H2-PAT)
 Abstract:
            Subsequent to the discovery that the (+)-benzomorphan sigma receptor ligands,
            (+)-pentazocine and (+)-N-allylnormetazocine, stimulated tyrosine hydroxylase activity and
            dopamine synthesis in rat striatum in vitro, we reported a similar effect on a structurally
            similar series of 1-phenyl-3-aminotetrahydronaphthalenes (phenylaminotetralins,
            PAT's).Both racemic 1-phenyl-3-dimethylamino-6-chloro-7-hydroxytetralin (Cl,OH-PAT)
            and racemic 1-phenyl-3-dimethylaminotetralin (H2-PAT) stimulated tyrosine hydroxylase
            with an EC50 of aproximately 0.1 mM .The former was also found to have a non-specific
            dopamine releasing effect while the latter was devoid of such activity affording it the less
            complicated pharmacological profile of the two analogs.We previously reported the
            synthesis of tritium labeled Cl,OH-PAT to be used in radioreceptor and autoradiography
            studies and found that it labelled a sigma-like site in guinea pig brain with an apparent Kd
            of ca. 50 pM and with a pharmacological profile unique from other known CNS
            receptor.Here we report the synthesis of high specific activity tritium labeled
            trans-(1R,3S)-(-)-H2-PAT as this enantiomer was found to be more active in the tyrosine
            hydroxylase assay and possessed approximately 45 fold greater affinity for the novel
            neuromodulatory sigma-like receptor.Key Words: 1-phenyl-3-aminotetralins, tritium,
            sigma-like receptor, tyrosine hydroxylase, dopamine, H2-PAT
 CNR:
            5856058

 Author:
            Mokrosz, J. L.; Bojarski, A. J.; Mackowiak, Marzena; Bielecka, Zofia; Boksa,
            J.
 Reference:
            Journal, PHARAT, Pharmazie, EN, 49, 5, 1994, 328-333
 Title:
            Structure-activity relationship studies of CNS agents. Part 10:
            1-Aryl-2-<3-(4-aryl-1-piperazinyl)propyl>-1,4-dihydro-3(2H)-isoquinolinones:
            Two modes of the interaction with the 5-HT1A receptor site
 Abstract:
            The synthesis and 5-HT1A and 5-HT2 receptor affinities of
            1-aryl-2-<3-(4-aryl-1-piperazinyl)propyl>-1,4-dihydro-3(2H)-isoquinolinones
            7-28 are reported.The two derivatives 7 and 13 were the most potent 5-HT1A
            ligands (Ki 1.72 +/- 0.07 and 2.75 +/- 0.59 nM, respectively) of all the
            investigated compounds.It has been found that the effect of the substituent in
            the 1-arylpiperazine portion is opposite to the observed in simple
            1-arylpiperazine.The molecular modelling results indicate that the
            investigated derivatives may interact with 5-HT1A sites in two different ways:
            as ordinary 4-substituted 1-arylpiperazines, or in such a manner that the aryl
            substituent at position 1 of the 3(2H)-isoquinolinone moiety and N-4
            piperazine atom mimics remarkably well the bioactive conformation of
            simple 1-arylpiperazines.
 CNR:
            5894272

 Author:
            Savelli, Francesco; Boido, Alessandro; Satta, Margherita; Peana,
            Alessandra; Marzano, Cristina
 Reference:
            Journal, FRMCE8, Farmaco, EN, 49, 4, 1994, 259-266
 Title:
            SYNTHESIS AND CNS ACTIVITIES OF PYRIDOPYRAZINONE AND
            PYRIDODIAZEPINONE DERIVATIVES
 Abstract:
            New tricyclic derivatives with cyclocondensed pyrido-pyrazine 7,10
            and pyrido-diazepine 20a,20b skeletons were synthetized and
            biologically investigated.The compounds, preliminarily tested on
            explorative, muscle relaxing, antinociceptive, spontaneous motor
            activities and influence on the narcotic effect of Evipan, revealed
            interesting CNS depressant and analgesic activities.The
            pyrido<2,3-e>pyrrolo<1,2-a>pyrazine structure of 7 appeared the most
            promising for analgesic and neuroleptic activities.The above
            compounds were assayed also for their capacity to inhibit DNA
            synthesis in Ehrlich ascites tumor cells; 20a appeared to be able of
            inducing a significant inhibition.
 CNR:
            5894511

 Author:
            Hoffman, Amnon; Pinto, Evelyne; Afargan, Mishel; Schattner, Amichai
 Reference:
            Journal, JPMSAE, J.Pharm.Sci., EN, 83, 4, 1994, 559-561
 Title:
            Cyclosporine Enhances Theophylline Neurotoxicity in Rats
 Abstract:
            Treatment with cyclosporine may be associated with adverse central
            nervous system (CNS) effects as well as with the potentiation of effects
            of certain other drugs.In particular, theophylline-induced seizures,
            which are often fatal and occur unpredictably over a wide range of
            serum theophylline concentrations, may be precipitated.To study this
            interaction, adult rats that were injected with cyclosporine or placebo
            (50 mg/kg in a single dose or on each of four consecutive days)
            received a constant infusion of theophylline (2 mg/min iv) until the
            onset of maximal seizures.At that time, blood, cerebrospinal fluid
            (CSF), and brain tissue samples were obtained for theophylline
            concentration determinations by HPLC , as well as for measurement of
            several biochemical parameters in the serum.Consecutive
            cyclosporine administration (but not a single dose) reduced serum
            protein levels.There was a small increase in theophylline sensitivity
            after a single dose of cyclosporine.The CSF theophylline
            concentrations at the onset of seizures were 215 +/- 10 vs 202 +/- 5
            mg/L (P < 0.04); however, sequential cyclosporine treatment resulted
            in significant lowering of the CSF theophylline concentrations required
            to produce convulsions (231 +/- 8 vs 191 +/- 10, P < 0.001).Likewise,
            the drug concentrations at the onset of convulsions in both the brain
            and serum were significantly lower in cyclosporine-treated rats than in
            control animals.Thus, cyclosporine treatment may be a predisposing
            factor for theophylline toxicity and increase the risk for generalized
            seizures.
 CNR:
            5894585

 Author:
            Vega, S.; Gil, M.S.; Darias, V.; Mateo, C.C. Sanchez; Exposito, M.A.; et
            al.
 Reference:
            Journal, EJMCA5, Eur.J.Med.Chem.Chim.Ther., EN, 29, 3, 1994,
            233-240
 Title:
            5,6-Dihydro-1H,4H-pyrazolo<4,3-f>pyrrolo<1,2-a><1,4>diazepines.
            Synthesis and pharmacological evaluation
 Abstract:
            A series of new
            5,6-dihydro-1H,4H-pyrazolo<4,3-f>pyrrolo<1,2-a><1,4>diazepines was
            synthesized and tested for acute toxicity and CNS activity in
            mice.Some of these compounds were shown to possess anxiolytic
            activity similar to that of diazepam with weak anticonvulsant and
            sedative action. pyrazolo<4,3-f>pyrrolo<1,2-a><1,4>diazepine/
            anxiolytic activity
 CNR:
            5898584

 Author:
            Mule, A.; Pirisino, G.; Moretti, M. D.; Savelli, F.; Boido, A.; et al.
 Reference:
            Journal, BCFAAI, Boll.Chim.Farm., EN, 133, 3, 1994, 167-172
 Title:
            Cyclopenta<e><1,5>benzodiazepin-10(9H)-one derivatives as CNS
            depressant agents
 Abstract:
            A series of dialkylaminoalkyl derivatives of
            cyclopenta<e><1,5>benzodiazepin-10(9H)-one (E1-4) and its 6-chloro
            derivative (E5-8) was prepared to evaluate their CNS activity in
            comparison with that of isosteric pyridodiazepinones (A1-4) previously
            described.The results of the pharmacological screening show a
            significant depressant activity more remarkable in 6-chloro derivatives,
            which also revealed a high and lastind analgesic activity.The
            replacement of pyridine with benzene nucleus did not show any
            significant or homogeneous activity variation.KEY-WORDS:
            Dialkylaminoalkyl derivatives; Cyclopenta-diazepine;
            1,5-benzodiazepine; Cyclopenta-benzodiazepine
 CNR:
            5899280

 Author:
            Wuensch, Bernhard; Zott, Matthias; Hoefner, Georg
 Reference:
            Journal, TETRAB, Tetrahedron, EN, 50, 27, 1994, 8003-8010
 Title:
            Benzomorphan Analogous CNS Agents: Synthesis of Homochiral
            Epoxybenzocyclooctenamines
 Abstract:
            The crucial steps in the preparation of the enantiomerically pure amine
            5 from the enol ester 3 are: 1.Stereoselective reduction of the enol
            ester 3 to give the b-hydroxy ester 6; 2. elimination of the hydroxy
            group of 6 according to the method of Barton and McCombie;
            3.Hofmann rearrangement of the amide 12 with
            <bis(trifluoroacetoxy)iodo>benzene to yield the ammonium chloride
            14*HCl.In contrast to the racemic amines (+/-)-1a and (+/-)-2a the
            homochiral amine 5 did not influence the behaviour of mice.Therefore,
            we conclude that 5 after intraperitoneal application has no effects on
            the central nervous system.
 CNR:
            5902520

 Author:
            Tsuzuki, Noriko; Hama, Teruo; Kawada, Mitsuhiro; Hasui, Akihiro;
            Konishi, Ryoji; et al.
 Reference:
            Journal, JPMSAE, J.Pharm.Sci., EN, 83, 4, 1994, 481-484
 Title:
            Adamantane as a Brain-Directed Drug Carrier for Poorly Absorbed
            Drug. 2. AZT Derivatives Conjugated with the 1-Adamantane Moiety
 Abstract:
            Five AZT (azidothymidine) prodrugs conjugated with the
            1-adamantane moiety via an ester bond were synthesized to improve
            the transport of AZT into the central nervous system (CNS).In in vitro
            degradation studies with rat and human plasma, it was demonstrated
            that the prodrugs were degradated enzymatically and converted
            quantitatively to their parent drug, AZT.As assessed by octanol-buffer
            partitioning, the prodrugs were much more lipophilic than AZT and
            were expected to penetrate the blood-brain barrier (BBB) readily.In in
            vivo studies, in which the prodrugs were administered intravenously to
            rat, the prodrugs in brain tissue were detected at 7-18 times higher
            concentrations than AZT in spite of the negligible amount of the
            prodrug in the cerebrospinal fluid.These results indicate that the
            introduction to AZT of the 1-adamantane moiety results in the
            enhancement of the BBB penetration.This pharmaceutical approach
            would be beneficial for the efficient treatment of the CNS infection by
            human immunodeficiency virus.
 CNR:
            5904485

 Author:
            Eiden, Fritz; Denk, Felix; Hoefner, Georg
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), GE, 327, 7, 1994,
            405-412
 Title:
            CNS-Active Pyrans: Amine- and Aryl-Substituted
            6,8-Dioxabicyclooctanes
 Abstract:
            The amin- and phenyl substituted 6,8-dioxabicyclooctanes 10 and 11
            show distinct CNS-activities.Intensity and profile depend on the type of
            amine and the stereochemistry of the products.Therefore, we have
            synthesized 6,8-dioxabicyclooctanes with different amine-phenyl
            distances and examined their CNS-activities on mice as well as by
            receptor binding studies with the PCP-binding site which is part of the
            NMDA-receptor-complex.
 CNR:
            5904759

 Author:
            Vanotti, E.; Fiorentini, F.; Villa, M.
 Reference:
            Journal, JHTCAD, J.Heterocycl.Chem., EN, 31, 4, 1994, 737-744
 Title:
            Synthesis of Novel Derivatives of 1H-Imidazo<1,2-b>Pyrazole as
            Potential CNS-Agents
 Abstract:
            As part of a preliminary study of novel 5-HT3 ligands, the synthesis of a
            series of 1H-imidazo<1,2-b>pyrazole derivatives is described.The
            bicyclic heteroaromatic nucleus was functionalized at positions 1, 6
            and 7 to give the series of tropanyl derivatives 4a-g, 12a, 12d (Table
            1).Different synthetic approaches were utilized to obtain the desired
            molecules: endo and exo 6-amides 4a, 12a and 6-ester 4b required
            two independent schemes due to the opposite behavior of the
            intermediate imidazolide 3 towards tropine and tropanamine.The
            7-congeners, ester 4c, its tropinium salt 4e, the endo and exo amides
            4d and 12d were prepared from the known common precursor 8 <1>,
            while derivatives 4f-g, originated by functionalizing position 1, were
            obtained from 1H-imidazo<1,2-b>pyrazole by direct N-acylation.Since
            the structural features of these molecules seemed to meet the main
            rules of the S.A.R. studies published so far <2-5>, they were evaluated
            "in vitro" for 5-HT3 receptor affinity (Table 2).The biochemical data
            show significant activity for derivatives 4a-e, 4g.These results are
            encouraging and justify further investigational work on this class of
            molecules.
 CNR:
            5907352

 Author:
            Jurayj, Jurjus; Haugwitz, Rudiger D.; Varma, Ravi K.; Paull, Kenneth
            D.; Barrett, John F.; Cushman, Mark
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 37, 14, 1994, 2190-2197
 Title:
            Design and Synthesis of Ellipticinium Salts and 1,2-Dihydroellipticines
            with High Selectivities against Human CNS Cancers in Vitro
 Abstract:
            9-Methoxy-2-methylellipticinium acetate (6), along with the 9-methyl
            and 9-chloro derivatives (7, and 8, respectively) have shown
            remarkable selectivities in vitro against the NCI human CNS cancer
            subpanel.In order to target these types of compounds to the CNS in
            vivo, a series of 1,2-dihydroellipticines was synthesised.
            9-Methoxy-2-methyl-1,2-dihydroellipticine (9) retained the potency and
            selectivity of the parent compound 6 but was unstable toward oxidation
            to 6.In order to improve the stability of 9, it was converted to the
            vinylogous amide 33 by introduction of a for myl group in the
            4-position.Compound 33 proved to be much more stable than 9, but it
            was also less potent than 9 by about 1 order of magnitude, and it was
            less selective for the CNS subpanel than 9.To overcome the limited
            water solubilities of the ellipticines and dihydroellipticines, several
            ellipticine analogues incorporating polar groups on the N-2 nitrogen
            were prepared.The 2-(methoxymethyl)ellipticinium salts 24 and 25, as
            well as the (methylthio)methyl congener 26, were relatively potent
            anticancer agents which displayed cytotoxicity selectivity profiles
            similar to compound 6.The cytotoxic dihydroellipticines 9 and 10
            exhibited potencies approaching that of ellipticine itself in facilitating
            the formation of a "cleavable complex", while the least cytotoxic
            ellipticine derivatives exhibited no cleavage above background.
 CNR:
            5908294

 Author:
            Mokrosz, Jerzy L.; Duszynska, Beata; Paluchowska, Maria H.
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), EN, 327, 8, 1994,
            529-532
 Title:
            Structure-Activity Relationship Studies of CNS Agents, XV:
            N-<w-(4-Aryl-1-piperazinyl)alkyl>-2-oxo-1,2,3,4-tetrahydroquinolines
            and -4-oxo-1,2,3,4-tetrahydropyrazino<1,2-a>indoles: New, Highly
            Potent 5-HT1A Ligands
 Abstract:
 CNR:
            5925133

 Author:
            Mokrosz, J. L.; Mokrosz, Maria J.; Bojarski, A. J.; Charakchieva-Minol,
            Sijka
 Reference:
            Journal, PHARAT, Pharmazie, EN, 49, 10, 1994, 781-782
 Title:
            Structure-activity relationship studies of CNS agents. Part 16: A lower
            limit of a distance between crucial pharmacophores of 5-HT1A ligands
 Abstract:
 CNR:
            5925313

 Author:
            Mokrosz, J. L.; Strekowski, L.; Duszynska, Beata; Harden, D. B.;
            Mokrosz, Maria J.; Bojarski, A. J.
 Reference:
            Journal, PHARAT, Pharmazie, EN, 49, 11, 1994, 801-806
 Title:
            Structure-activity relationship studies of CNS agents. Part 14:
            Structural requirements for the 5-HT1A and 5-HT2A receptor selectivity
            of simple 1-(2-pyrimidinyl)piperazine derivatives
 Abstract:
            The 5-HT1A and 5-HT2A receptor affinity of model
            1-(2-pyrimidinyl)piperazine derivatives 15-21 and 23-32 has been
            determined. 2-(N-Methylpiperazino)-4,6-di(2-thienyl)pyrimidine 26 is a
            new, highly active and selective 5-HT2A receptor ligand.The
            topography of a molecule and the stereoelectronic effects of the
            thiophene rings are the major factors responsible for the high affinity
            and selectivity of 26 towards 5-HT2A sites.
 CNR:
            5925350

 Author:
            Pinza, Mario; Pifferi, Giorgio
 Reference:
            Journal, FRMCE8, Farmaco, EN, 49, 11, 1994, 683-692
 Title:
            SYNTHESIS AND BIOTRANSFORMATION OF
            3-HYDRAZINOPYRIDAZINE DRUGS
 Abstract:
            Several derivatives of 3-hydrazinopyridazine are reported to possess
            interesting biological properties as chemotherapeutics,
            anti-inflammatory agents, CNS depressants and stimulants and
            anti-hypertensives.In particular, variously substituted
            3-hydrazinopyridazines raised considerable interest as peripheral
            vasodilators with improved potency and safety compared to
            hydralazine and dihydralazine.More recently, some compounds
            bearing substituents which may also account for b-adrenoceptor
            blocking properties were prepared and studied in approaches aimed at
            combining in single molecules both the vasodilating and the
            b-adrenoceptor blocking activity in an appropriate balance.When
            substituents are alkylic or arylic, the pyridazine nucleus is synthesized
            through the appropriate 4-oxoacid, otherwise 3,6-dichloropyridazine is
            generally used as starting compound.In the latter case, while the
            nucleophilic substitution of the first chlorine atom is easily obtained,
            the reactivity of the second chlorine is considerably reduced when the
            first group introduced has electrodonating properties (alkoxy or
            alkylamino groups) and an excess of hydrazine is required under
            forcing conditions.Since 3-chloro-6-hydrazinopyridazine is practically
            unreactive, it was found to be convenient to convert it to
            3-chloro-6-(triphenylmethylazo)pyridazine, whose halogen atom is
            activated towards nucleophiles, and to restore the hydrazino group
            after the substitution. 3-Hydrazinopyridazines are extensively
            metabolized, mainly by acetylation of the free hydrazino group,
            followed by cyclization, or by reaction with endogenous carbonyl
            compounds and, to a lower extent by hydrolysis or oxidation.When the
            hydrazino group is protected, biotransformation is generally less
            extensive, giving rise to an active metabolite which in turn follows the
            metabolic pathways outlined above.Interestingly, pharmacokinetic
            studies on cadralazine (a 3-hydrazinopyridazine protected as
            ethoxycarbonyl derivative) support the attractive hypothesis that the
            pro-drug is biotransformed topically to the active metabolite in the
            endothelium of arterial vessels, close to the site at which smooth
            muscle relaxation is required.
 CNR:
            5925559

 Author:
            Anderson, Wayne K.; Gopalsamy, Ariamala; Reddy, Peech S.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 37, 13, 1994, 1955-1963
 Title:
            Design, Synthesis, and Study of 9-Substituted Ellipticine and
            2-Methylellipticinium Analogues as Potential CNS-Selective Antitumor
            Agents
 Abstract:
            N,N-Dimethylformamide (DMF) dineopentyl acetal-mediated
            O-alkylations of 9-hydroxyellipticine gave 9-ethoxy-,
            9-(1-methylethoxy)-, and 9-(1,1-dimethylethoxy)ellipticine (3a, 4a, and
            5a, respectively). Methylation of the O-alkylellipticines gave the
            corresponding N-methylpyridinium iodides (3b, 4b, and 5b). The
            iodides were converted to the acetates (3c, 4c, and 5c) by
            ion-exchange resin. Attempts to prepare
            9-(2,2,2-trifluoroethoxy)ellipticine (6a) using the DMF acetal gave
            10-(2,2,2-trifluoroethoxy)-9-hydroxyellipticine (8a).
            9-(2,2,2-Trifluoroethoxy)- and 9-phenoxyellipticine (6a and 7a,
            respectively) were prepared by total synthesis. The ellipticines and
            N-methylellipticinium derivatives were evaluated for in vitro antitumor
            activity against a panel of human tumors.
            2-Methyl-9-(1,1-dimethylethoxy)ellipticinium acetate (5c) was inactive,
            but all of the other compounds exhibited significant antitumor activity.
            The ellipticines showed no significant subpanel specificity; however,
            the N-methylellipticinium compounds tested did exhibit specificity for
            the CNS tumor subpanel.
 CNR:
            5927349

 Author:
            Darias, V.; Abdallah, S. S.; Tello, M. L.; Delgado, L. D.; Vega, S.
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), EN, 327, 12, 1994,
            779-784
 Title:
            NSAI Activity Study of
            4-Phenyl-2-thioxo-benzo<4,5>thieno<2,3-d>pyrimidine Derivatives
 Abstract:
            A series of 4-phenyl-2-thioxo-benzo<4,5>thieno<2,3-d>pyrimidine
            derivatives endowed with anti-inflammatory and related
            pharmacological properties were submitted to a more extensive study
            to know their exact pharmacological profile and their possible side
            effects.The studied compounds possess a remarkable analgesic
            activity, devoid of central effects.They also show an interesting
            anti-inflammatory profile evidenced by their effectiveness in different
            experimental models of inflammation.In addition, these compounds
            exhibit none or very little activity on CNS, scarce toxicity and low
            gastrointestinal agressivity.
 CNR:
            5944303

 Author:
            Malabarba, Adriano; Ciabatti, Romeo; Kettenring, Juergen; Ferrari,
            Pietro; Scotti, Roberto; et al.
 Reference:
            Journal, JANTAJ, J.Antibiot., EN, 47, 12, 1994, 1493-1506
 Title:
            AMIDES OF DE-ACETYLGLUCOSAMINYL-DEOXY TEICOPLANIN
            ACTIVE AGAINST HIGHLY GLYCOPEPTIDE-RESISTANT
            ENTEROCOCCI. SYNTHESIS AND ANTIBACTERIAL ACTIVITY
 Abstract:
            Removal, by selective reduction, of the acetylglucosamine from
            teicoplanin A2-2 (CTA/2) produced the
            34-de(acetylglucosaminyl)-34-deoxy pseudoaglycone (II).This
            compound was more active in vitro than CTA/2 against
            coagulase-negative staphylococci (CNS).Amide derivatives obtained
            by condensation of the carboxyl group of II with primary amines were
            particularly active against Streptococcus pyogenes and had some in
            vitro activity against VanA enterococci highly resistant to both
            teicoplanin and vancomycin.Among them, a carboxamide (VII) with a
            branched tetramine also had better activity than the corresponding
            amide of teicoplanin against CNS.In contrast, the dimethylamide (VIII)
            of II had little activity against VanA enterococci.While the overall
            structure of the heptapeptide backbone of the secondary carboxamides
            of II is the same as in CTA/2 and its amide derivatives, in deoxy
            pseudoaglycone II and its tertiary amide VIII the 51,52-peptide bond
            undergoes a conformational change from the original cisoid to the
            transoid orientation.This difference between the secondary amides of II
            and dimethylamide VIII is reflected in their different antibacterial
            spectrum.The direct synthesis of the amides of deoxy pseudoaglycone
            II from parent CTA/2-amides by reaction with sodium borohydride is
            also described.
 CNR:
            5944355

 Author:
            Vega, Salvador; Gil, M. Soledad
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), EN, 327, 11, 1994,
            721-728
 Title:
            4H-Pyrrolo<1,2-a>thieno<3,2-f> and
            4H-pyrrolo<1,2-a>thieno<2,3-f><1,4>diazepines: Synthesis and
            Pharmacological Evaluation
 Abstract:
            As an extension of a previous work, in which a number of
            4H-pyrrolo<1,2-a>thieno<2,3-f><1,4>diazepines were described, a
            new series of derivatives of the isomeric
            pyrrolo<1,2-a>thieno<3,2-f>diazepines ring system has been
            synthesized.The products obtained, together with those reported in the
            previous paper, were tested for acute toxicity and CNS activity in mice.
 CNR:
            5944532

 Author:
            Hoffman, Amnon; Habib, Gustav; Gilhar, Dalia; Zohar, Hila
 Reference:
            Journal, JPPMAB, J.Pharm.Pharmacol., EN, 46, 9, 1994, 760-764
 Title:
            Cyclosporin Increases the CNS Sensitivity to the Hypnotic Effect of
            Phenobarbitone but not Ethanol in Rats
 Abstract:
            The purpose of this investigation was to determine whether repetitive
            administration of cyclosporin affects the pharmacodynamics of
            phenobarbitone- and ethanol-induced anaesthesia.Sabra male rats
            received either cyclosporin (50 mg kg-1 day-1, i.m.) for four days, or the
            same volume of the vehicle.Two hours after the last cyclosporin dose,
            phenobarbitone or ethanol solutions were infused intravenously at a
            constant rate until the onset of anaesthesia.Repetitive treatment with
            cyclosporin increased the CNS sensitivity to the hypnotic action of
            phenobarbitone.This was evidenced by the lower CSF phenobarbitone
            concentration, at the onset of the hypnotic effect, in the
            cyclosporin-treated group vs control values (115+/-4 vs 93+/-7 mg L-1,
            P=0.01).However, the same pretreatment had no apparent effect on
            the pharmacodynamics of ethanol-induced sleep.It is suggested that
            anaesthesiologists must be alert to the possible increase in brain
            sensitivity when placing cyclosporin patients under anaesthesia with
            barbiturates.
 CNR:
            5945831

 Author:
            Pawlowski, Maciej; Drabczynska, Anna; Gorczyca, Maria; Malec, Danuta;
            Modzelewski, Jerzy
 Reference:
            Journal, APPHAX, Acta Pol.Pharm., EN, 51, 4-5, 1994, 385-392
 Title:
            SYNTHESIS AND PHARMACOLOGICAL SCREENING OF NOVEL
            10-SUBSTITUTED DIAZEPINO-<2,1-f>PURINES
 Abstract:
            Two series of N10 substituted derivatives of
            1,3-dimethyl-2,4,9-trioxo-1,3,6,7,8,10-hexahydro-1,3-diazepino-<2,1-f>-purine
            and
            1,3-dimethyl-2,4-dioxo-1,3,6,7,8,9-hexahydro-10H-1,3-diazepino-<2,1-f>-purine
            were synthesized and tested for CNS activity.The most active in central nervous
            system tests were compounds <II> and <XIV>.Keywords: N10 substituted
            diazepino-<2,1-f>-purines, synthesis, elemental analysis, pharmacological
            effect.
 CNR:
            5946859

 Author:
            Iwasaki, Nobuhiko; Sakaguchi, Jun; Ohashi, Tetsuo; Takahara, Eiji;
            Ogawa, Nobuo; et al.
 Reference:
            Journal, CPBTAL, Chem.Pharm.Bull., EN, 42, 11, 1994, 2276-2284
 Title:
            Amphoteric Drugs. I. Synthesis and Antiallergic Activity of
            <4-(Diphenylmethoxy)piperidino>-, <4-(Diphenylmethyl)piperazinyl>-
            and <4-(Diphenylmethylene)piperidino>alkanoic Acid Derivatives
 Abstract:
            A simple method of transforming classical antihistaminics into
            nonsedative antiallergic agents with strong effects in rat models is
            described.Various <4-(diphenylmethoxy)piperidino>- (series A),
            <4-(diphenylmethyl)piperazinyl>- (series B) and
            <4-(diphenylmethylene)piperidino>alkanoic acid derivatives (series C)
            were synthesized and examined for antiallergic activities and effects
            on the central nervous system (CNS), in comparison with the
            corresponding N-methyl derivatives (1a-c).N-Alkylcarboxylic acids
            (5a-c) showed stronger inhibitory effects on compound 48/80-induced
            lethality in rats than the corresponding N-methyl derivatives (1a-c).In
            particular, N-alkylcarboxylic acids (5a) in series A exhibited
            approximately 100-fold stronger inhibitory effects than 1a, and were the
            least effective in prolonging the sleeping time on hexobarbital-induced
            anesthesia in mice in all series.As a result of chemical modification in
            series A, it was found that introduction of a methyl group at the
            para-position on one benzene ring in the (diphenylmethoxy)piperidine
            system effectively reduced CNS side-effects without reducing
            antiallergic activity.
            (+)-3-<4-<(4-Methylphenyl)phenylmethoxy>piperidino>propionic acid
            ((+)-5l), an optically active isomer of 5l, exhibited a stronger antiallergic
            effect (ED50 = 0.17 mg/kg, p.o.) than ketotifen and terfenadine in the 48
            h homologous passive cutaneous anaphylaxis (PCA) test, and
            moreover exhibited no CNS side-effects, such as prolongation of the
            sleeping time on hexobarbital-induced anesthesia, at an oral dose of
            30 mg/kg.Compound (+)-5l was thus proved to be a promising
            candidate as a nonsedative antiallergic agent.Keywords amphoteric
            drug; zwitter-ionization; antiallergic agent; classical antihistaminic;
            N-alkylcarboxylic acid; diphenylmethoxypiperidine
 CNR:
            5948849

 Author:
            Malinka, Wieslaw; Sieklucka-Dziuba, Maria; Raitar-Cynke, Grazyna;
            Borowicz, Kinga; Kleinrok, Zdzislaw
 Reference:
            Journal, FRMCE8, Farmaco, EN, 49, 12, 1994, 783-792
 Title:
            STUDIES ON SYNTHESIS AND BIOLOGICAL PROPERTIES OF
            PYRAZOLO<4,3-c>-PYRIDO<3,2-e>-1,2-THIAZINE-5,5-DIOXIDE
            BEARING 4-SUBSTITUTED-1-PIPERAZYNYLPROPYL MOIETY
 Abstract:
            Derivatives of the pyrazolopyridothiazine-5,5-dioxide 6 and the
            pyridothiazine-1,1-dioxide 2 bearing
            4-phenyl-(heteroaryl)-1-piperazinylpropyl substituent at the nitrogen of
            the thiazine ring were synthesized.The acute toxicity and preliminary
            results of the CNS activity of some derivatives 2 and 6 are described.A
            structure-activity relationship is discussed.
 CNR:
            5956551

 Author:
            Iwasaki, Nobuhiko; Sakaguchi, Jun; Ohashi, Tetsuo; Yamazaki,
            Masahiro; Ogawa, Nobuo; et al.
 Reference:
            Journal, CPBTAL, Chem.Pharm.Bull., EN, 42, 11, 1994, 2285-2290
 Title:
            Amphoteric Drugs. II. Synthesis and Antiallergic Activity of
            <4-(5H-Dibenzo<a,d>cyclohepten-5-ylidene)piperidino>alkanoic Acid
            Derivatives and Related Compounds
 Abstract:
            A simple method of transforming classical tricyclic antihistaminics into
            nonsedative antiallergic agents with equal potency in rats and
            guinea-pigs is described.A series of
            <4-(5H-dibenzo<a,d>cyclohepten-5-ylidene)piperidino>alkanoic acid
            derivatives (6a) and related compounds (6b-f) were synthesized and
            examined for antiallergic and antihistaminic activities and effects on
            the central nervous system (CNS) in comparison with the
            corresponding N-methyl derivatives (2a-f).N-Alkylcarboxylic acids
            (6a-f) showed stronger inhibitory effects on 48 h homologous passive
            cutaneous anaphylaxis (PCA) in rats than 2a-f, and also were less
            effective in prolongation of the sleeping time on hexobarbital-induced
            anesthesia in mice in comparison with 2a-f.As a result of further
            modification, it was found that introduction of an oxygen atom into the
            central ring of the tricyclic system in amphoteric compounds enhanced
            their antiallergic and antihistaminic activities.
            3-<4-(6H-Dibenz<b,e>oxepin-11-ylidene)piperidino>propionic acid
            (6c) exhibited strong inhibitory effects on 48 h homologous PCA in rats
            (ED50 = 0.067 mg/kg, p.o.) and on histamine-induced
            bronchoconstriction in anesthetized guinea-pigs (ED50 = 0.0085
            mg/kg, p.o.), and thus is a promising candidate as an antiallergic
            agent. Keywords amphoteric drug; zwitter-ionization; antiallergic agent;
            classical tricyclic antihistaminic; dibenzo<a,d>cycloheptene;
            dibenzo<b,e>oxepin
 CNR:
            5960834

 Author:
            Somlai, Cs.; Balaspiri, L.
 Reference:
            Journal, JPCCEM, J.Prakt.Chem./Chem.-Ztg., EN, 336, 6, 1994,
            525-529
 Title:
            Synthesis of Analogues of Thyrotropin-Releasing Hormone
 Abstract:
            The synthesis of ten new thyrotropin-releasing hormone analogues
            (15-24) which contain uncoded amino acids (L- and D-homoleucine, L-
            and D-homophenylalanine, L-homoproline and 6-ketopipecolic acid) is
            described here.The peptide bond formation was achieved in solution
            phase using pentafluorophenyl ester activation of the N-protected
            amino acids.The analogues were tested for their ability to release
            thyrotropin and for CNS activities and proved to be fully inactive.
 CNR:
            5962183

 Author:
            Abdel-Rahman, R. M.; Seada, M.; Fawzy, M.; El-Baz, Ibrahim
 Reference:
            Journal, FRMCE8, Farmaco, EN, 48, 3, 1993, 397-406
 Title:
            SYNTHESIS OF SOME NEW THIOETHERS OF
            1,2,4-TRIAZINE-3-HYDRAZONES AND ASSAYS FOR THEIR
            ANTICANCER AND ANTIHUMAN IMMUNE VIRUS ACTIVITIES
 Abstract:
            A number of various thioethers derived from
            3-hydrazone-5,6-diphenyl-1,2,4-triazines have been synthesized and
            evaluated for anticancer and anti HIV activities.The structures are
            supported by elemental analysis, IR, UV and 1H-NMR spectral
            data.Most of the tested compounds displayed a sigificant activity
            against Leukemia/Lymphoma, CNS, Ovarian and Small cell lung
            cancer.
 CNR:
            5751010

 Author:
            Lee, Moses; Rhodes, Andrea L.; Wyatt, Michael D.; D'Incalci, Maurizio;
            Forrow, Stephen; Hartley, John A.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 36, 7, 1993, 863-870
 Title:
            In Vitro Cytotoxicity of GC Sequence Directed Alkylating Agents
            Related to Distamycin
 Abstract:
            Imidazole containing analogues 7, 10, and 17 of distamycin wherein
            the C-terminus contain a dimethylamino moiety have been shown to
            selectively bind to the minor groove of GC-rich sequences.
            Accordingly, these agents were employed as vectors for the delivery of
            a variety of alkylating agents to GC-rich sequences. The alkylating
            agents are attached to the N-terminus of these vectors thus providing
            the benzoyl N-mustards (8, 15, and 18 that contain one, two, and three
            imidazole units, respectively) and substituted acetamides 11-14.
            Results from the ethidium displacement assay for the formamides 7,
            10, and 17 and mustards 15 and 18 showed that these agents bind to
            calf thymus DNA, poly(dA.dT), poly(dG.dC), and also to coliphage T4
            DNA, thus confirming their binding in the minor groove. The reduced
            binding constants of these compounds for poly(dA.dT) while still
            binding as strongly, or more strongly, to poly(dG.dC) than distamycin
            provided evidence for their acceptance of GC sequences. Selectivity
            for GC-rich sequences was also indicated by CD titration studies.
            Titration of 10, 15, 17, and 18 to poly(dA.dT) produced weak
            drug-induced CD bands at ca. 330 nm; however, interaction of these
            agents to poly(dG.dC) in equimolar drug concentrations gave strong
            bands in this region. Results from dialysis and cross-link gel
            experiments provided evidence of alkylation and cross-linking of DNA
            by the mustards which could explain their enhanced cytotoxicity over
            the formamido analogues. The bifunctional N-mustard-containing
            analogues 5 and 18 are significantly more cytotoxic than the
            monoalkylating acetamides 11-14. The mustards also exhibited
            significant activity against cell lines derived from solid tumors such as
            melanomas, ovarian cancers, CNS cancers, and small cell lung
            cancer.
 CNR:
            5754212

 Author:
            Bonnaud, B.; Carlessi, A.; Bigg, D. C. H.
 Reference:
            Journal, JHTCAD, J.Heterocycl.Chem., EN, 30, 1, 1993, 257-265
 Title:
            Synthesis of Novel Isoquinoline Derivatives as Potential CNS-Agents
 Abstract:
            A series of 4-aminomethyl-1,2,3,4-tetrahydroisoquinoline derivatives
            were prepared as potential CNS-agents acting via amino-acid
            neurotransmitter systems. The compounds were synthesized from
            1,2,3,4-tetrahydro-1-oxoisoquinoline-4-carboxylic acids obtained by
            dipolar cycloaddition reactions of imines with homophthalic anhydride.
            Among the compounds tested 5c and 5m showed sub-micromolar
            affinity for the NMDA receptor and represent a structurally novel class
            of ligand for this site.
 CNR:
            5754249

 Author:
            Tripathi, M.; Verma, M.; Gujrati, V. R.; Palit, G.; Shanker, K.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 43, 6, 1993, 632-635
 Title:
            Thiazolidine Congeners as Central Nervous System Active Agents
 Abstract:
            3-(Benzylideneamino)-2-imino-4-thiazolidinones (IIa-c) synthesized by
            cyclization of substituted thiosemicarbazones (Ia-c) were converted into
            2-amino-3-(substituted benzylamino)-4-thiazolidinones (IIIa-c),
            2-imino-3-(a-arylazobenzylidene)amino-4-thiazolidinones (IVa-f) and
            2-(2-amino-4-oxo-3-thiazolidinyl)-3-aryl-4-isothiazolidinones (VIa-c), IVa-f were
            finally converted into
            5-(arylaminomethyl)-2-imino-3-(a-arylazobenzylidene)-amino-4-thiazolidinones
            (Va-l).These compounds III, V and VI were evaluated for their monoamine
            oxidase (MAO) inhibitory activity in vitro and various CNS activities in
            vivo.Some of the compounds exhibited promising CNS activity. Key words:
            Antidepressants; thiazolidinone derivatives, pharmacology, synthesis.
 CNR:
            5756573

 Author:
            Matsushita, M.; Yonemori, F.; Furukawa, N.; Ohta, A.; Toide, K.; et al.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 43, 8, 1993, 813-817
 Title:
            Effects of the Novel Thyrotropin-releasing Hormone Analogue
            Na-((1S,2R)-2-Methyl-4-oxocyclopentylcarbonyl)-L-histidyl-L-prolinamide
            Monohydrate on the Central Nervous System in Mice and Rats
 Abstract:
            The central nervous system (CNS) effects of a novel thyrotropin-releasing
            hormone (TRH) analogue, JTP-2942
            (Na-((1S,2R)-2-methyl-4-oxocyclopentylcarbonyl)-L-histidyl-L-propilamide
            monohydrate, CAS 131404-34-7) were investigated and compared with
            those of TRH.When administrated subcutaneously, JTP-2942 was about
            80 times more potent than TRH in the antagonization of reserpine-induced
            hypothermia, and when administrated intravenously it was about 16 times
            more potent than TRH in the potentiation of flexor reflexes.Furthermore,
            oral administration of JTP-2942 was able to antagonize a
            chlorpromazine-induced reduction in locomotor activity, while TRH was far
            less effective.In tests on the recovery from pentobarbital-induced sleep
            and disturbance of consciousness induced by concussive head trauma,
            JTP-2942 was about 30 and 3 times more potent than TRH,
            respectively.Thus, JTP-2942 had a far stronger and more persistent action
            compared with TRH in regard to these effects.However, JTP-2942 had a
            3-fold lower effect on thyroid stimulating hormone (TSH) release than
            TRH.These results suggest that the stimulatory effects of JTP-2942 are
            selective for the CNS and that this TRH analogue may be applicable to
            clinical use.Key words: CAS 131404-34-7 .Central nervous system
            .JTP-2942
            .Na-((1S,2R)-2-Methyl-4-oxocyclopentylcarbonyl)-L-histidyl-L-prolinamide
            monohydrate, pharmacology .Thyrotropin-releasing hormone, analogue
 CNR:
            5808420

 Author:
            Tripodi, A. S.; Contos, S.; Germogli, R.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 43, 8, 1993, 877-880
 Title:
            Pharmacological Studies on Taurohyodeoxycholic Acid
 Abstract:
            In this study we investigated the anticholelithogenic and choleretic,
            activities and the general pharmacological action of
            taurohyodeoxycholic acid (THDCA, Io<*>, Praxis<*>, CAS 2958-04-5),
            a new biliary acid advocated for use as anticholelithogenic
            agent.THDCA had no significant activity on the CNS (spontaneous
            locomotor activity, body temperature, coordinated movement,
            respiration); it also had no significant anticonvulsant or central
            anticholinergic actions.With regard to the action on the cardiovascular
            system, THDCA administration did not give rise to significant changes
            in blood pressure or ECG.Investigation of its action on the
            gastrointestinal system revealed no significant changes in he intestinal
            transport of charcoal after treatment.However, biliary flow and biliary
            solids content were increased by THDCA intraduodenal doses of 300
            mg/kg b.w.In mice fed with lithogenic diet THDCA administration (230
            and 450 mg/kg b.w. for 8 weeks) significantly decreased gallstone and
            steatosis incidence.Key words: Biliary acids * CAS 2958-04-5 * Io<*> *
            Praxis<*> * Taurohyodeoxycholic acid, general pharmacology
 CNR:
            5808752

 Author:
            Erker, Thomas
 Reference:
            Journal, JHTCAD, J.Heterocycl.Chem., EN, 30, 3, 1993, 807-810
 Title:
            Studies on the Chemistry of Thieno-anellated O,N- and S,N-containing
            Heterocycles. 2. Synthesis of Thieno<2,3-b>diazepine Derivatives with
            Potential CNS Activity
 Abstract:
            Thieno-anellated compounds analogous to Clobazam (1) <2> and the
            nootropic 2 and 3 were synthesized.Thus, nucleophilic substitution on
            halogenated nitrothiophene derivatives with aniline and reaction with
            ethyl malonyl chloride gave after cyclisation the
            thieno<2,3-b>diazepinedione derivatives 7 and 14.These compounds
            were methylated to give the thieno-anellated heterocycles 8 and 9.
 CNR:
            5813164

 Author:
            Parsons, Simon; Passmore, Jack; White, Peter S.
 Reference:
            Journal, JCDTBI, J.Chem.Soc.Dalton Trans., EN, 10, 1993, 1499-1508
 Title:
            5,5'-Bi(1,3,2,4-dithiadiazolylium)(2+) Bis<hexafluoroarsenate(V)>: a
            General Synthetic Strategy to Molecules and Radicals containing
            Thiazyl Rings
 Abstract:
            The salt <SNS><AsF6> undergoes a quantitative multiple
            cycloaddition reaction with cyanogen to give the planar,
            centrosymmetric dication <formula>, which has been characterised by
            vibrational and 13C NMR spectroscopy, chemical analysis and X-ray
            crystallography.While the reaction between cyanogen and SNS(1+)
            must proceed via a 1:1 cycloadduct, <formula>, this was not prepared
            or observed.The cycloaddition of SNS(1+) to <formula> must therefore
            be kinetically preferred, contrary to arguments based on simple frontier
            molecular orbital (FMO) theory.By contrast, the reaction of
            <SNS><AsF6> with <formula> to give <formula> was complete only
            after 10 weeks at 50 deg C, in complete accord with FMO theory.These
            results are rationalised in terms of the influence of high-energy,
            in-plane molecular orbitals and the electrostatic interaction between
            SNS(1+) and the slightly negatively charged nitrogen atom (N) in the
            <formula> ring, which facilitates the second cycloaddition.The salt
            <formula> potentially provides access to a new family of eight other
            bicyclic CNS dications, radical cations and diradicals, of which
            <formula>, <formula> and <formula> are reported.
 CNR:
            5817853

 Author:
            McCormick, Kevin D.; Kobayashi, Kazumi; Goldin, Stanley M.; Reddy,
            N. Laxma; Meinwald, Jerrold
 Reference:
            Journal, TETRAB, Tetrahedron, EN, 49, 48, 1993, 11155-11168
 Title:
            Characterization and Synthesis of a New Calcium Antagonist from the
            Venom of a Fishing Spider
 Abstract:
            A new calcium antagonist, CNS 2103, is isolated from the venom of a
            fishing spider, Dolomedes okefinokensis.The structure of this
            compound is derived from spectroscopic data, including tandem mass
            spectrometry.A flexible, convergent synthesis of CNS 2103 is
            described.
 CNR:
            5842729

 Author:
            Khudyakov, Igor V.; McGarry, Peter F.; Turro, Nicholas J.
 Reference:
            Journal, JPCHAX, J.Phys.Chem., EN, 97, 1993, 13234-13242
 Title:
            A Time-Resolved Electron Spin Resonance and Laser Flash
            Spectroscopy Investigation of the Photolysis of Benzaldehyde and
            Benzoin in Homogenous Solvents and Micellar Solutions
 Abstract:
            Both photochemical a-cleavage of triplet benzoin (BZ) and hydrogen
            abstraction by triplet benzaldehyde (BA) from ground-state
            benzaldehyde produce geminate radical pairs of identical chemical
            structure.A search for "memory effects" in the chemically identical
            geminate radical pairs generated from different photochemical
            pathways was examined using the techniques of time-resolved
            electron spin resonance (TRESR) and time-resolved optical
            absorption spectroscopy.Photolysis of BZ in homogeneous organic
            solvents and in sodium dodecyl sulfate (SDS) micellar solutions leads
            to chemically induced dynamic electron polarization (CIDEP) of
            benzoyl and a-hydroxybenzyl radicals consisting of a strong emission
            (E) due to the triplet mechanism (TM) in the generation of electron
            polarization.Photolysis of BA in hydrogen-donating organic solvents
            results in a E/A (or E*/A) CIDEP pattern of a-hydroxybenzyl radicals
            due to the radical pair mechanism (RPM).In solvents which are poor
            hydrogen donors (benzene, acetonitrile) and/or at relatively high
            concentrations of BA, the photoreduction of triplet BA by ground-state
            BA generates benzoyl and a-hydroxybenzyl radicals, which manifest
            an E/A CIDEP spectrum assigned to RPM.Photoreduction of BA by
            KCNS in aqueous acetonitrile results in absorptive (A) CIDEP of
            a-hydroxybenzyl radicals, assigned to a rare case of RPM for which the
            g factor difference overwhelms the hyperfine interactions of the
            pertinent radical pair (the a-hydroxybenzyl and the (CNS)2.-
            radical).Computer simulation allows the estimation of the g factor of
            this inorganic polarized radical to be in the range 2.015 < g <
            2.03.Under conditions of low occupancy number of BA, the photolysis
            of BA in SDS micellar solution displayed CIDEP spectra assigned to a
            spin-correlated geminate radical pair (SCRP) consisting of
            a-hydroxybenzyl and alkyl radicals of SDS.At a higher occupancy
            number, a different SCRP spectrum is observed and is assigned to a
            polarized a-hydroxybenzyl and benzoyl radical pair.Computer
            simulation confirms all of the proposed assignments.Measurements of
            the decay kinetics of the a-hydroxybenzyl radical, observed by
            time-resolved absorption spectroscopy, show that the application of an
            external magnetic field of 0.30 T leads to a decrease in the rate of
            micellized geminate recombination in the photoreduction of micellized
            BA and to an increase in the rate of radical escape.No significant
            magnetic field effect was found on the decay of the a-hydroxybenzyl
            radicals produced from BZ.These results imply that radicals formed by
            a-cleavage of triplet BZ escape from micelles faster than the
            chemically identical geminate pair generated by the photoreduction of
            triplet BA by ground-state BA.
 CNR:
            5842873

 Author:
            Malinka, Wieslaw; Tatarczynska, Ewa
 Reference:
            Journal, FRMCE8, Farmaco, EN, 48, 7, 1993, 933-948
 Title:
            SYNTHESIS AND PHARMACOLOGICAL PROPERTIES OF
            N-(4-SUBSTITUTED-1-PIPERAZINYLALKYL)-1-BUTYL-2,5-DIMETHYLPYRROLE-3,4-DICARBOXYIMIDE
            DERIVATIVES
 Abstract:
            The preparation of a number of
            N-(4-substituted-1-piperazinylalkyl)-1-butyl-2,5-dimethylpyrrole-3,4-dicarboxyimides (3) is described.The
            structures of the novel compounds were confirmed by elemental and spectral analyses.The results of a
            preliminary pharmacological study of CNS effects caused by compounds 3 are reported.
 CNR:
            5844525

 Author:
            Wuensch, Bernhard; Hoefner, Georg; Bauschke, Gerd
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), GE, 326, 9, 1993,
            513-518
 Title:
            Synthesis and CNS-Activity of Spirocyclic Pethidine and Prodine
            Analogues
 Abstract:
            The bromoacetals 5a and 5b react with n-butyllithium and the
            piperidone 7 to yield the hydroxyacetals 8b and 8c,
            respectively.Cyclization of 8b and 8c followed by acid hydrolysis
            affords the spirocyclic hemiacetals 10b and 10c which are oxidized by
            PCC to give the spirocyclic prodine analogues 4b and 4c. - The
            corresponding spirocyclic pethidine derivative 2 is prepared by
            alkylation of the 2-benzopyran-3-one 16 with N-Lost (17).In the mouse
            writhing test the spiropethidine 2 is not analgesic active up to a dose of
            20 mg/kg body weight (bw).In the spirocyclic prodine series the
            methylated lactone 4c is the most active analgesic with an ED50-value
            (ED50 = 9.2 mg/kg bw) in the range of the ED50-value of tramadol.
 CNR:
            5844534

 Author:
            Wuensch, Bernhard; Zott, Matthias; Hoefner, Georg
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), GE, 326, 10, 1993,
            823-830
 Title:
            Synthesis of Homochiral 5,9-Epoxybenzocyclooctenes with
            Aminosubstituents: Relationship between Structure and CNS-Activity
 Abstract:
            This paper deals with the synthesis and psychopharmacological
            effects of variations of the sedative and analgesic tricyclic amines 3a
            and 3b: Starting with the homochiral ketone 4 the amines 5 (primary
            amino group in equatorial position), 7 (axially oriented dimethylamino
            group), 9 (additional phenyl residue in position 7), 13b, and 14b
            (equatorially and axially arranged dimethylaminomethyl group) and 23
            and 24 (axial amino group shifted to position 9) are prepared.BBr3
            cleaves the phenolic ethers of the secondary amine (+/-)-3a to yield the
            aminodiphenol (+/-)-10. - Keeping mice under observation for
            behavioral anomalies (Irwin screen) and analgesic activity (writhing
            test) shows, that the amines 5, 7, 9, (+/-)-10, 13b, 14b, and 23 do not
            reach the sedative and analgesic effects of the amines 3a and 3b,
            described by us.y
 CNR:
            5844761

 Author:
            Veng-Pedersen, Peter; Modi, Nishit B.
 Reference:
            Journal, JPMSAE, J.Pharm.Sci., EN, 82, 9, 1993, 918-926
 Title:
            Application of Neural Networks to Pharmacodynamics
 Abstract:
            Neural networks (NN) are computational systems implemented in
            software or hardware that attempt to simulate the neurological
            processing abilities of biological systems.A synopsis is presented of
            the operational characteristics, structures, and applications of NN.The
            NN technology has primarily been aimed at recognition science (e.g.,
            handwriting, voice, signal, picture, image, pattern, etc.).It is pointed out
            that NN may also be particularly suitable to deal with pharmacokinetc
            (PK) and pharmacodynamic (PD) systems, especially in cases such
            as multivariate PK/PD population kinetics when the systems are so
            complex that modeling by a conventional structured model building
            technique is very troublesome.The main practical advantage of NN is
            the intrinsic ability to closely emulate virtually any multivariate system,
            including nonlinear systems, independently of structural/physiologic
            relevance.Thus, NN are most suitable to model the behavior of
            complex kinetic systems and unsuitable to model a structure.In a
            practical sense, this structure limitation may be inconsequential
            because NN in its multivariate formulation may consider any
            physiologic, clinical, or population variable that may influence the
            kinetic behavior.The application of NN in PD is demonstrated in terms
            of the ability of an NN to predict, by extrapolation the central nervous
            system (CNS) activity of alfentanil.The drug was infused by a complex
            computer-controlled infusion scheme over 180 min with simultaneous
            recording of the CNS effect quantified by a fast Fourier transform
            power spectrum analysis.The NN was trained to recognize (emulate)
            the drug input-drug effect behavior of the PD system with the
            input-effect data for the 180 min as a training set.The trained NN was
            then used to predict, by extrapolation, the CNS effect in the subsequent
            120-min period that contained a complex infusion scheme to provide
            an extra challenge in testing how well the trained NN could predict the
            effect.The relative prediction performance of the NN was 66percent
            (SD = 32, n = 6), which indicates an excellent prediction considering
            the intrinsic high degree of fluctuations in the effect variable.The NN
            was best in predicting the high intensity effects and also learned to
            recognize an overshoot phenomenon indicative of development of
            short-term tolerance.
 CNR:
            5844966

 Author:
            Troschuetz, Reinhard; Gruen, Lothar
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), GE, 326, 11, 1993,
            857-864
 Title:
            Synthesis of Basically Substituted
            5H-Pyrimido<4,5-c>-2-benzazepines
 Abstract:
            The potentially CNS-active title compounds 19a-c can be prepared by
            a nine step synthesis beginning with phthalaldehydic
            acid.Knoevenagel condensation of 5 with the acetonitriles 2a-g and
            subsequent reduction with NaBH4 lead to the dihydrocinnamic acid
            nitriles 3.Only 3a can be cyclized to the 2-benzazepinnitriles
            9a,b.Ammonolysis of 9a yields the enaminonitrile 10, which is reacted
            with the orthoesters 11a-c to the imidic acid esters 12a-c.Ammonolysis
            leads to the tricycles 16a,b.After transformation of the lactam group in
            16 to an imidoyl chloride 17, aminolysis with the amines 18a-c
            provides the title compounds 19a-c.
 CNR:
            5844986

 Author:
            Stjernloef, P.; Elebring, T.; Andersson, B.; Svensson, A.; Svensson, K.;
            et al.
 Reference:
            Journal, EJMCA5, Eur.J.Med.Chem.Chim.Ther., EN, 28, 9, 1993,
            693-702
 Title:
            5-, 6-, 7-, And
            8-amino-2-<N,N-di-n-propylamino)-1,2,3,4-tetrahydronaphthalenes:
            centrally acting DA and 5-HT1A agonists
 Abstract:
            5-, 6-, 7- and
            8-Amino-2-(N,N-di-n-propylamino)-1,2,3,4-tetrahydronaphthalene were
            synthesized and compared with the corresponding phenolic
            compounds in vivo and in vitro for their effects on central serotonergic
            (5-HT1A) and dopaminergic (D2) systems.The 5- and 8-amino isomers
            surprisingly showed a 100-fold lower affinity for D2 and 5-HT1A
            receptors, respectively, than their corresponding phenols.This was
            also reflected in vivo.The 6-amino and hydroxy-isomers were
            equipotent, while the 7-amino compound showed in vivo effects both
            on dopaminergic and serotoner gic systems, the latter not being
            noticed in vitro.Intermediates
            8-bromo-2-(N,N-di-n-propylamino)-1,2,3,4-tetrahydronaphthalene and
            2-(N,N-di-n-propylamino)-1,2,3,4-tetrahydronaphthalene-8-carboxylic
            acid methyl ester were also tested and found to be quite potent 5-HT1A
            agonists. synthesis/ aminotetralins/ anilines/ serotonergic/
            dopaminergic/ agonists/ 5-HT1A/ D2 binding/ 5-HTP accumulation/
            DOPA-accumulation/ CNS
 CNR:
            5848352

 Author:
            Gilly, C.; Taillandier, G.; Pera, M.H.; Luu-Duc, C.; Rousseau, A.; et al.
 Reference:
            Journal, EJMCA5, Eur.J.Med.Chem.Chim.Ther., EN, 28, 11, 1993,
            905-910
 Title:
            Synthesis and evaluation of pharmacological CNS activity of
            a-hydroxy O-aklyl etheroximes
 Abstract:
            a-cetol etheroximes/ O-alkyl etheroximes/ analgesic activity/
            anticonvulsant/ anti-inflammatory compound
 CNR:
            5849019

 Author:
            Gruska, A.; Franke, R.; Vogel, M.; Herrmann, D.; Hegenscheid, B.;
            Presber, W.
 Reference:
            Journal, PHARAT, Pharmazie, EN, 48, 12, 1993, 950-951
 Title:
            Substructures of CNS pharmaceuticals show additional antiprotozoan
            action
 Abstract:
 CNR:
            5852397

 Author:
            Bojarski, A. J.; Cegla, M. T.; Charakchieva-Minol, Sijka; Mokrosz, Maria
            J.; Mackowiak, Marzena; et al.
 Reference:
            Journal, PHARAT, Pharmazie, EN, 48, 4, 1993, 289-294
 Title:
            Structure-activity relationship studies of CNS agents. Part9: 5-HT1A
            and 5-HT2 receptor affinity of some 2- and 3-substituted
            1,2,3,4-tetrahydro-b-carbolines
 Abstract:
            The 5-HT1A and 5-HT2 receptor affinity of 2- and 3-substituted
            1,2,3,4-tetrahydro-b-carbolines 1-8, 10 and 12-15 has been
            determined.It has been found that the specific 5-HT1A affinity of the
            protonated form (KiAH+) of 2-n-hexyl derivatives 4, 8, 14 and (+)-LSD is
            of the same order.It has been shown by means of molecular modelling
            methods that pharmacophores of all the active compounds can adopt
            a common position at the 5-HT1A receptor model.The model also
            offers an explantation for the observed stereoselectivity of chiral
            compounds.
 CNR:
            5852627

 Author:
            Skibo, Edward B.; Schulz, William G.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 36, 21, 1993, 3050-3055
 Title:
            Pyrrolo<1,2-a>benzimidazole-Based Aziridinyl Quinones. A New Class
            of DNA Cleaving Agent Exhibiting G and A Base Specificity
 Abstract:
            Pyrrolo<1,2-a>benzimidazole(PBI)-based aziridinyl quinones cleave
            DNA under reducing conditions specifically at G + A bases without any
            significant cleavage at C + T bases.The postulated mechanisms
            involve phosphate alkylation by the reductively activated aziridine to
            afford a hydrolytically labile phosphotriester as well as the classic N(7)
            purine alkylation followed by depurination and backbone
            cleavage.Evidence is presented that the phosphate alkylation
            mechanism could contribute.The PBIs possess a unique spectrum of
            cytotoxity against cancer cells (inactive against leukemia but active
            against nonsmall cell lung, colon, CNS, melanoma, ovarian, and renal
            cancers).Also reported are results of in vivo antitumor activity screens.
 CNR:
            5853700

 Author:
            Singh, O. V.; Sangeeta; Khanna, M. S.; Garg, C. P.; Kapoor, R. P.; et al.
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 32, 12, 1993, 1241-1248
 Title:
            Synthesis of 2,3-disubstituted-6-<1-acyl-5-aryl (or
            hetaryl)-4,5-dihydropyrazol-3-yl>chromones of potential medicinal
            interest
 Abstract:
            The title compounds (12-19) have been synthesized by the
            condensation of 2,3-disubstituted-6-<(3-aryl or
            hetaryl)acryloyl>chromones (8-11) with hydrazine hydrate in the
            presence of formic or acetic acid.Their structures have been elucidated
            on the basis of elemental analyses and spectral data.Some of the
            compounds have also been screened for their anticomplementary,
            CNS and antiinflammatory activities.
 CNR:
            5853940

 Author:
            Bansal, O. P.; Srinivas, J. S.; Singh, P. P.; Junnarkar, A. Y.
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 32, 8, 1993, 901-902
 Title:
            Synthesis and pharmacology of some new
            2-arylamino-4-oxo<1,3>thiazino<5,6-b>quinoxalines
 Abstract:
            Several new 2-arylamino-4-oxo<1,3>thiazino<5,6-b>quinoxaline (II)
            have been synthesized by reacting ethyl
            2-chloroquinoxaline-3-carboxylate (I) with various arylthioureas.The
            compounds possess CNS depressant activity.
 CNR:
            5855032

 Author:
            Khadilkar, B. M.; Samant, S. D.
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 32, 11, 1993, 1137-1142
 Title:
            Synthesis and pharmacology of
            2-<3-(4-aryl-1-piperazinyl)-2-hydroxypropyl/3-oxopropyl/propoxy>-1H-isoindole-1,3(2H)-diones
 Abstract:
            The potassium salt of 1H-isoindole-1,3(2H)-dione (1) on treatment with
            1-chloro-2,3-epoxypropane furnishes 2-(oxiranylmethyl)-1H-isoindole-1,3(2H)-dione (2) which
            on reaction with 1-arylpiperazines (3) affords
            2-<3-(4-aryl-1-piperazinyl)-2-hydroxypropyl>-1H-isoindole-1,3(2H)-diones (4).The later
            compounds (4) are also obtained by reacting 3 with
            2-(3-chloro-2-hydroxypropyl)-1H-isoindole-1,3(2H)-dione (6) which in turn is obtained by
            treating 1H-isoindole-1,3(2H)-dione with 1-chloro-2,3-epoxypropane.
            2-Acetyl-1H-isoindole-1,3(2H)-dione on reaction with 3 in the presence of formaldehyde gives
            2-<(4-aryl-1-piperazinyl)methyl>-1H-isoindole-1,3(2H)-diones (9). 1,3-Isobenzofuranedione (12)
            on condensation with 3-aminopropanoic acid (13) furnishes
            3-(1H-isoindole-1,3(2H)-dion-2-yl)propanoic acid (14) which on conversion into its acid chloride
            (15) followed by condensation with 3 afford
            2-<3-(4-aryl-1-piperazinyl)-3-oxopropyl>-1H-isoindole-1,3(2H)-diones (16).
            2-Hydroxy-1H-isoindole-1,3(2H)-dione (17) is reacted with 1,3-dibromopropane to obtain
            2-(3-bromopropoxy)-1H-isoindole-1,3(2H)-dione (21) which on condensation with 3 affords
            2-<3-(4-aryl-1-piperazinyl)propoxy>-1H-isoindole-1,3(2H)-diones (23).Compounds 4, 16 and 23
            show 50-80percent decrease in the blood pressure of anaesthetised cats at 1 mg/kg.Two of
            them show 50percent decrease in BP at 0.01 mg/kg and have LD50 200 mg/kg.All the
            compounds show mild CNS depressant activity.
 CNR:
            5855289

 Author:
            Ambrogi, Valeria; Grandolini, Giuliano; Perioli, Luana; Giampietri,
            Antonio
 Reference:
            Journal, FRMCE8, Farmaco, EN, 48, 5, 1993, 653-664
 Title:
            STUDIES ON ANNELATED 1,4-BENZOTHIAZINES AND
            1,5-BENZOTHIAZEPINES. VI. Synthesis and preliminary
            pharmacological evaluation of
            1-alkylaminomethyl-4,5-dihydro-s-triazolo<3,4-d>-1,5-benzothiazepines
 Abstract:
            A series of new 1-alkylaminomethyl derivatives of
            4,5-dihydro-s-triazolo<3,4-d>-1,5-benzothiazepines has been prepared
            using chloromethyltriazolobenzothiazepines 4a-g as key intermediates.
            - The 1-alkylaminomethyl derivatives were tested for CNS activity on
            mice and some of them caused remarkable decrease of spontaneous
            motor activity.
 CNR:
            5894737

 Author:
            Yongue, Brandon G.
 Reference:
            Journal, STEDAM, Steroids, EN, 58, 12, 1993, 594-604
 Title:
            Strategies for investigation of CNS mechanisms of phenotypic
            variation in blood pressure and salt appetite in genetic hypertensive
            rats
 Abstract:
            Several characteristics of spontaneously hypertensive rats (SHR) and
            normotensive Wistar-Kyoto rats (WKY), make these homozygouts
            strains particularly well suited for investigating the interactions of salt
            appetite, blood pressure control, and their neuroendocrine
            substrates.Appropriate genetic and developmental investigations of
            sources of variation in salt appetite, blood pressure, and their putative
            neuroendocrine substrates in these homozygous strains can provide
            valuable insights into fundamental mechanisms of disease, as well as
            factors controlling homeostatic behavioral and physiological
            processes.However, inappropriate use of these strains can produce
            misleading, although seductively plausible, conclusions regarding
            mechanisms.Selective inbreeding for hypertension has concentrated
            in SHR the "high pressure" allele for several genes that influence
            blood pressure, whereas breeding for normal blood pressure has left
            WKY with the "normal pressure" allele for all or most of these genes.In
            principle, inbred hypertensive strains could provide information about
            specific genetic alterations that mediate the hyperstensive
            phenotype.The benefits of work with these strains are discussed, but
            several false assumptions and logical pitfalls are described that might
            cause misleading or erroneous interpretations of results from work with
            such strains.These problems illustrate the importance of the research
            strategy in elucidating the particular information that can be provided
            by these inbred animal models of hypertension.Two strategic
            approaches for studying hypertension and other genetically
            determined or influenced characteristics in inbred animal models such
            as SHR are discussed: cosegregation analysis for identifying or
            rejecting genetic linkage, j and brain graft techniques for identifying
            brain specific genetic influences on cardiovascular or behavioral
            phenotypes.Examples of each approach are described. (Steroids
            58:594-604, 1993). Keywords: Hypertension; salt appetite,
            cosegregation; angiotensinogen; neural graft; spontaneously
            hypertensive rats
 CNR:
            5896469

 Author:
            Nicholls, Ian A.; Alewood, Paul F.; Brinkworth, Ross I.; Morrison, Stuart
            F.; Andrews, Peter R.
 Reference:
            Journal, JRMPDM, J.Chem.Res.Miniprint, EN, 10, 1993, 2811-2826
 Title:
            2-Substituted 1,3-Benzodiazocines: Design, Synthesis and Evaluation
            as Potential Central Nervous System Active Agents
 Abstract:
            Hybridisation of the structures of the antihypertensive clonidine 1 with
            the anxiolytic diazepam 2 led to the novel 2-imino-1,3-benzodiazocine
            3.Conformational analysis of 3 and comparison to a previously
            established pharmacophore for CNS activity revealed favourable
            compatibility.CNS receptor binding analysis of 3, and some
            2-substituted derivatives, demonstrated a preference for the
            a-adrenoceptors.
 CNR:
            5931022

 Author:
            Baindur, Nandkishore; Tran, Mai; Niznik, Hyman B.; Guan, H. C.; Seeman,
            Phillip; Neumeyer, John L.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 35, 1, 1992, 67-72
 Title:
            (+/-)-3-Allyl-7-halo-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines
            as Selective High Affinity D1 Dopamine Receptor Antagonists: Synthesis
            and Structure-Activity Relationship
 Abstract:
            Substituted 1-phenyl-3-benzazepines form a class of compounds
            possessing potent and selective affinity for the D1 DA receptor.
            7,8-Dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF 38393)
            and its 6-halo analogues are potent and selective D1 receptor
            agonists.Recently, the 3-allyl derivatives of SKF 38393 and its analogues
            were described as selective D1 agonists with higher D1 efficacy and CNS
            potency.In order to extend these results to compounds in the
            7-halo-8-hydroxy-substituted antagonist series, we have synthesized and
            pharmacologically characterized3-allyl analogues of 7-substituted (Cl, Br, H)
            8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines.These 3-allyl
            derivatives were compared with their 3-methyl and 3-unsubstituted
            analogues in terms of their D1 receptor affinity and selectivity.The results
            have been used to generate structure-affinity relationships.The D1 receptor
            affinity, for 3-substitution, is found to be in the order: methyl > allyl > H.For
            7-substitution, the affinity is in the order: Cl = Br > H.The 3-allyl compounds
            show affinity close to that of the parent (3-methyl) compounds while
            exhibiting a slightly diminished D1 selectivity.However, the greater
            lipophilicity of the 3-allyl compounds may enable them to cross the
            blood-brain barrier more readily and thereby exhibit higher in vivo CNS
            potency.Thus 3-allylbenzazepines have potential as high affinity selective
            D1 antagonists.
 CNR:
            5595149

 Author:
            Nozulak, Joachim; Vigouret, Jean M.; Jaton, Anne L.; Hofmann, Alfred;
            Dravid, Anant R.; et al.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 35, 3, 1992, 480-489
 Title:
            Centrally Acting a1-Adrenoceptor Agonists Based on
            Hexahydronaphth<2,3-b>-1,4-oxazines and
            Octahydrobenzo<g>quinolines
 Abstract:
            Centrally acting a1-agonists may be of therapeutic value in dementias
            and other CNS disorders characterized by symptoms of noradrenergic
            insufficiency.Therefore, on the basis of known peripherally acting
            a1-agonists two new groups of centrally acting a1-agonists with
            improved lipophilicity, the hexahydronaphth<2,3-b>-1,4-oxazines type
            A and the octahydrobenzo<g>quinolines type B were designed.The
            N-methylated derivatives 14 and 33 demonstrate potent, direct
            agonistic activity at postjunctional a1-receptors.Ring substituent
            alterations in compounds of type A and B change the potency of
            compounds on the rabbit ear artery by over 3 orders of magnitude (pD2
            = 5.35-8.40).The efficacy of these compounds varies from 42 to
            110percent.Those a1-agonists which were selective in the pithed rat
            increase vigilance in rats.Compound 14 was found to be a centrally
            acting a1-agonist with good tolerability in different animal species and
            in healthy volunteers.Furthermore, 14 selectively stimulates the
            breakdown of phosphatidylinositol in rat cerebral cortex slices.In vivo,
            the compound reverses behavioral deficits in animals which received
            noradrenergic lesions following DDC and DSP4 treatment.Oxazine 14
            and its close derivatives are by far more lipophilic than commonly
            known a1-agonists.This is demonstrated in a ClogP-PROBIS plot.
 CNR:
            5596518

 Author:
            Migliara, O.; Flugy, A.; Novara, V.; Gagliano, M.
 Reference:
            Journal, FRMCE8, Farmaco, EN, 47, 1, 1992, 111-120
 Title:
            SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF SOME
            PYRAZOLO<3,4-e><1,4>DIAZEPIN-4,7-DIONES
 Abstract:
            The synthesis of two new pyrazolo<3,4-e><1,4>diazepin-4,7-diones
            and pharmacological test to investigate their eventual behavioural
            central nervous system (CNS) effects were reported.
 CNR:
            5601717

 Author:
            Eiden, Fritz; Kainz, Alexander
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), GE, 325, 1, 1992,
            17-22
 Title:
            CNS-Agents: Synthesis and Properties of 3-Anilino-8-oxatropanes
 Abstract:
            Reaction of the 8-oxabicyclooctenone and -octanone derivatives 3 and
            4 with aniline and metal hydrides yields the 3a-isomers of the aniline
            derivatives 7 and 8, preferably.The configuration can be determined by
            NMR-spectroscopy and by cyclization to the scopoline analogue
            9b.Depending on the N-substitution the pyran rings of the a-isomers
            are flattened (7,8) or deformed to give a boat conformation
            (10,11,13).The conformationally restricted aniline derivative 18 can be
            obtained from 4 with 2-aminobenzaldehyde and diborane, trans
            configuration is preferred in 18.Some substrates reveal CNS-effects in
            mice.
 CNR:
            5602819

 Author:
            Sowell, J. Walter; Tang, Yunzhao; Valli, Matthew J.; Chapman, James
            M.; Usher, Laura A.; et al.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 35, 6, 1992, 1102-1108
 Title:
            Synthesis and Cholinergic Properties of
            Bis<<(dimethylamino)methyl>furanyl> Analogues of Ranitidine
 Abstract:
            The histaminergic H2 antagonist, ranitidine, has also been found to
            significantly inhibit acetylcholinesterase (AChE) in vitro.In an effort to
            develop novel, nonquaternary AChE inhibitors capable of penetrating
            into the CNS and alleviating the cholinergic deficit characteristic of
            Alzheimer's disease, a series of bis<<(dimethylamino)methyl>furanyl>
            analogues of ranitidine has been synthesized.All compounds were
            evaluated for human erythrocyte AChE inhibitory activity and
            compared to ranitidine, physostigmine, and
            tetrahydro-9-aminoacridine (THA).The most active AChE inhibitors
            were N,N'-disubstituted derivatives of 2-nitro-1,1-ethenediamine and
            4,6-dinitro-1,3-benzenediamine, with compound 8 demonstrating
            activity greater than physostigmine.Deletion of the diaminonitroethene
            group in a series of alkyl and aryl bis-thioethers, yielded a number of
            slighthly less active compounds, comparable in potency to THA.The
            13 most active AChE inhibitors all demonstrated a more selective
            inhibition of AChE, as opposed to butyrylcholinesterase inhibition, than
            did THA.Compounds 3 and 22 were equally active to THA in
            potentiating rat ileal contractions.Binding studies demonstrated M1 and
            M2 cholinergic receptor affinities slightly greater than or equal to
            THA.Differential receptor binding studies showed compound 12
            resembled THA in agonist/antagonist activity.Compounds 11-13
            significantly elevated mouse brain acetylcholine levels, when
            administered at 80percent of their approximate lethal doses, but were
            less active than THA or physostigmine.
 CNR:
            5644560

 Author:
            Eiden, Fritz; Kainz, Alexander; Gebhard, Rolf
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), GE, 325, 2, 1992,
            77-82
 Title:
            Synthesis, Reactions, and CNS-Activities of 6,7-Annulated
            8-Oxatropane Derivatives
 Abstract:
            The butadiene derivatives 10a-c react with the oxa-bicyclooctanone 9
            to give the cyclohexene annulated oxatropanes 11a-c.The
            acetoxyderivatives 11b and 11c can be transformed into the
            cyclohexadiene or benzene derivatives 13 and 12, respectively. 11a
            reacts with HN3 to afford the tricyclic oxazepanone 14 which can be
            reduced to give 15a; the oxime-tosylate 16b reacts with
            Al(CH3)3/DIBALH to yield the oxazepane 15c.Treatment of the
            oxabicyclooctanes 9 and 19 with benzonitrile oxide or diazomethane
            affords the isoxazoline or pyrazoline annulated oxatropanes 21, 22,
            and 20, respectively. 21 was reduced to the amino alcohol 23. 15c and
            23 show CNS-activity in the mouse.
 CNR:
            5649016

 Author:
            Takasuna, K.; Kasai, Y.; Usui, C.; Takahashi, M.; Hirohashi, M.; et al.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 42, 3A, 1992, 408-418
 Title:
            General Pharmacology of the New Quinolone Antibacterial Agent Levofloxacin
 Abstract:
            The general pharmacological properties of
            (-)-(S)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido<1,2,3-del><1,4>benzooxazine-6-carboxylic
            acid hemihydrate (levofloxacin, DR-3355, CAS 100986-85-4), an optically active isomer of ofloxacin, were examined.
            1.Central nervous system (CNC); DR-3355 at 200-600 mg/kg p.o. showed depressant activity on the CNS, as was indicated
            by the depressant syndrome (mice), decreased spontaneous motor activity (mice) and hypothermia (mice and rabbits).In the
            cat behavior and EEG experiments, it had both stimulant and depressant effects at 30-100 mg/kg i.p., and caused transient
            slow waves followed by seizures at 20-30 mg/kg i.v.DR-3355 had no effect on convulsion, hexobarbital anestesia, pain
            reaction to a tail pinch, or conditioned avoidance response, except that it showed mild analgesic activity in acetic acid
            writhing at 600 mg/kg p.o. 2.Respiratory and cardiovascular system: DR-3355 produced a hypertensive and bradycardiac
            effect after the rapid i.v. injection of 6 mg/kg or more in anestetized dogs, accompanied by an increase in plasma histamine
            concentration.Both changes were markedly reduced when the test drug was administered by continuous i.v. infusion.
            3.Autonomic nervous system: DR-3355 inhibited nictitating membrane contraction induced by both pre- and post-ganglionic
            stimulation, and inhibited the depressor response to acetylcholine at 20 mg/kg i.v.It had no influence on pupil size or on
            pressor response to norepinephrine. 4.Gastrointestinal system: DR-3355 at 600 mg/kg p.o. inhibited gastric secretion.Dog
            gastrointestinal motility was slightly inhibited, and was then stimulated over the dose range of 2-20 mg/kg i.v.It had no
            influence on gastrointestinal propulsion, the gastric emptying rate or the gastric mucosa. 5.Isolated smooth muscle: At a
            concentration of 5*10-4 g/ml, DR-3355 was devoid of spasmogenic or spasmolytic activity, except for showing a slight
            relaxation effect (trachea), inhibition of nicotine-induced contraction (ileum) and spontaneous or oxytocin-induced motility
            (pregnant uterus). 6.Miscellaneous: DR-3355 inhibited the urine output and carrageenin-induced paw edema at 600 mg/kg
            p.o.It had no effect on skeletal muscle contraction or the corneal reflex.
 CNR:
            5649739

 Author:
            Bansal, O P; Srinivas, J S; Sastry, C V Reddy
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 31, 4, 1992, 289-292
 Title:
            Synthesis and pharmacology of some new
            3,4-diaryl-5-aryloxymethyl-1,2,4-triazoles
 Abstract:
            Several 3,4-diaryl-5-aryloxymethyl-1,2,4-triazoles (VI) have been
            synthesized by cyclocondensation of appropriate methylthioimino
            derivatives (V) with arylcarbohydrazides in refluxing DMF, and
            screened for their CNS and antiinflammatory activities.Selected
            compounds have also been tested for their antibacterial and antifungal
            properities in vitro.Compound 13 is found to possess significant
            antidepressant activity while 4,7 and 19 display moderate
            antiinflammatory activity.The antidepressant activity of 13 has been
            studied in greater detail.
 CNR:
            5655066

 Author:
            Pathak, U S; Gandhi, N V; Singh, S; Warde, R P; Jain, K S
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 31, 4, 1992, 223-229
 Title:
            Synthesis of some <1,2,4>triazolo<4,3-a>thieno<3,2-e>pyrimidin-5(4H)-ones
 Abstract:
            A series of hitherto unreported
            1-(un)substituted-4-phenyl<1,2,4>triazolo<4,3-a>thieno<3,2-e>pyrimidin-5(4H)-ones
            (8a-k) have been synthesized by the condensation of
            2-hydrazino-3-phenylthieno<2,3-d>pyrimidin-4(3H)-ones (7a,b) with various
            one-carbon donors.Compounds, 8c and 8g, exhibit significant CNS depressant and
            analgesic activities, respectively.
 CNR:
            5655782

 Author:
            Ambrogi, Valeria; Giampietri, Antonio; Grandolini, Giuliano; Perioli,
            Luana; Ricci, Maurizio; Tuttobello, Lorenzo
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), EN, 325, 9, 1992,
            569-578
 Title:
            Studies on Annelated <1,4>Benzothiazepines, V: Synthesis and
            Biological Activity of N-2 Alkylamino Derivatives of
            4,5-Dihydro-s-triazolo<3,4-d>-1,5-benzothiazepine
 Abstract:
            The synthesis of a new series of N-2 alkylamino derivatives of
            4,5-dihydro-s-triazolo<3,4-d>-1,5-benzothiazepine has been
            accomplished starting from 2,3-dihydro-1,5-benzothiazepin-4(5H)ones
            and their 2-methyl and 2-aryl derivatives.All the compounds were
            tested in vitro for their antimicrobial activity, but none of them showed
            remarkable activity.The tricyclic compounds 7a-j, 8a-j, 9a-j, 10a-j, and
            11a-j were also screened for their CNS activity in mice and several of
            them showed interesting activity.
 CNR:
            5658703

 Author:
            Boksa, J.; Misztal, S.; Chojnacka-Wojcik, E.; Gastol-Lewinska, L.;
            Grodecka, A.; Mokrosz, J. L.
 Reference:
            Journal, PHARAT, Pharmazie, EN, 47, 4, 1992, 254-257
 Title:
            Structure-activity relationship studies of CNS agents --- Part 4:
            2-<3-(4-Aryl-1-piperazinyl)propyl>-1,2,3,4-tetrahydro-b-carbolin-1-one
            derivatives as potential central anti-serotonin agents
 Abstract:
            Seven derivatives of 1,2,3,4-tetrahydro-b-carbolin-1-one have been
            prepared.Three of them showed significant central anti-serotonin
            activity, comparable with that of trazodone or etoperidone.Some
            structural features were found to be important for the central
            antiserotonoin activity of the investigated class of compounds.
 CNR:
            5661667

 Author:
            Desta, Z.; Steingruber, M.
 Reference:
            Journal, PHARAT, Pharmazie, EN, 47, 7, 1992, 525-528
 Title:
            Pharmacodynamic interactions between isoniazed and theophylline in
            mice and rats, and the influence of pyridoxine
 Abstract:
            Convulsions induced by acute administration of isoniazid (1),
            theophylline (2) as well as combinations of 1 and 2 were evaluated in
            male albino mice and male Wistar rats.The effect of pyridoxine (3) on
            these seizures was tested.Serum and brain levels of 1 after
            coadministration with 2 and caffeine (4) were assessed.The relevance
            of the observed pharmacokinetic phenomena in serum is questionable
            for the CNS processes because animals convulsed late (starting 90
            min) and no significant changes of brain levels of 1 were observed.In
            conclusion, interactions of 1 and 2 may not occur through common
            mechanisms and exist only if the dose of 1 is toxic suggesting
            toxicological rather than therapeutic relevance.
 CNR:
            5663282

 Author:
            Ornstein, Paul L.; Schoepp, Darryle D.; Arnold, M. Brian; Augenstein,
            Nancy K.; Lodge, David; et al.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 35, 19, 1992, 3547-3560
 Title:
            6-Substituted Decahydroisoquinoline-3-carboxylic Acids as Potent and
            Selective Conformationally Constrained NMDA Receptor Antagonists
 Abstract:
            We have prepared a series of 6-substituted
            decahydroisoquinoline-3-carboxylic acids, and structurally similar
            analogs, as potential N-methyl-D-aspartate receptor antagonists.There
            is a large body of evidence to support the use of such compounds as
            cerebroprotective agents in a variety of acute and chronic
            neurodegenerative disorders, where some component of
            glutamate-mediated excitotoxicity may exist.The compounds prepared
            were evaluated in vitro in both receptor binding assays
            (<3H>CGS19755, <3H>AMPA, and <3H>kainic acid) and in a cortical
            wedge preparation (versus NMDA, AMPA, and kainic acid) to
            determine affinity, potency, and selectivity.The new amino acids were
            also evaluated in vivo for their ability to block NMDA-induced lethality
            in mice.We synthesized many of the possible diastereomers of the
            decahydroisoquinoline nucleus in order to examine the spatial and
            steric requirements for affinity at the NMDA receptor and activity as
            NMDA antagonists.From our structure-activity relationship we
            identified two potent and selective NMDA receptor antagonists, the
            phosphonate- and tetrazole-substituted amino acids 31a and 32a,
            respectively, that show good activity in animals following systemic
            administration.For example, 31a and 32a selectively displaced
            <3H>CGS19755 binding with IC50s of 55 +/- 14 and 856 +/- 136 nM,
            respectively, and selectively antagonized responses due to NMDA in a
            cortical wedge preparation with IC50s of 0.15 +/- 0.01 and 1.39 +/- 0.29
            mM, respectively.And compounds 31a and 32a blocked NMDA-induced
            lethality in mice with minimum effective doses of 1.25 and 2.5 mg/kg
            (intraperitoneal), respectively.These novel amino acids are among
            some of the most potent NMDA antagonists described thus far, and are
            excellent candidates for development as neuroprotective agents for a
            number of CNS disorders.
 CNR:
            5704316

 Author:
            Ichikawa, Nobuhiro; Naora, Kohji; Hayashibara, Masakazu; Katagiri,
            Yoshihiro; Iwamoto, Kikuo
 Reference:
            Journal, JPPMAB, J.Pharm.Pharmacol., EN, 44, 11, 1992, 915-920
 Title:
            Effect of Fenbufen on the Entry of New Quinolones, Norfloxacin and
            Ofloxacin, into the Central Nervous System in Rats
 Abstract:
            The entry of two new quinolone antibacterial agents, norfloxacin and
            ofloxacin, into the central nervous system (CNS) of rats, and the effect
            of fenbufen on this was investigated.At various times after the
            administration of a bolus intravenous dose of norfloxacin or ofloxacin
            (10 mg kg-1) with or without fenbufen (20 mg kg-1), serum and
            cerebrospinal fluid (CSF) samples and whole brain were collected
            from the rats and the concentration of norfloxacin or ofloxacin in each
            sample was determined.Serum concentrations of both quinolones
            declined biexponentially with time and were significantly elevated by
            coadministration with fenbufen at the terminal phase.The fractions of
            these quinolones bound to serum protein were not altered by
            coadministration with fenbufen.Coadministered fenbufen raised the
            brain concentrations of both quinolones but did not affect their brain to
            serum unbound concentration ratios.In contrast, CSF to serum
            unbound concentration ratios as well as CSF concentrations of
            norfloxacin and ofloxacin were elevated by coadministration with
            fenbufen.Apparent diffusional clearances between blood and CSF of
            norfloxacin and ofloxacin estimated by the physiological model
            analysis increased by 1.9 and 2.6 times, respectively, after
            coadministration with fenbufen.These findings suggest that
            coadministered fenbufen may facilitate the entry of norfloxacin and
            ofloxacin into the CNS.
 CNR:
            5705367

 Author:
            Bonnet, Pierre A.; Michel, Alain; Laurent, Florence; Sablayrolles,
            Claire; Rechencq, Eliane; et al.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 35, 18, 1992, 3353-3358
 Title:
            Synthesis and Antibronchospastic Activity of 8-Alkoxy- and
            8-(Alkylamino)imidazo<1,2-a>pyrazines
 Abstract:
            Theophylline still occupies a dominant place in asthma
            therapy.Unfortunatly its adverse central nervous system (CNS)
            stimulant effects can dramatically limit its use, and adjustments in the
            dosage are often needed.We have synthesized a new series of
            imidazo<1,2-a>pyrazine derivatives which are much more potent
            bronchodilators than theophylline in vivo and do not exhibit the CNS
            stimulatory profile.In vitro studies on isolated rat uterus and guinea pig
            trachea confirm the high potentialities of these derivatives.
            6-Bromo-8-(methylamino)imidazo<1,2-a>pyrazine-3-carbonitrile (23) is
            identified as the most potent compound of the series.As i n the case of
            theophylline, phosphodiesterase inhibition appears unlikely to be the
            unique mechanism of the action of this series of heterocycles.
 CNR:
            5705606

 Author:
            Valli, Matthew J.; Tang, Yunzhao; Kosh, J. W.; Chapman, James M.; Sowell,
            J. Walter
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 35, 17, 1992, 3141-3147
 Title:
            Synthesis and Cholinergic Properties of
            N-Aryl-2-<<<5-<(dimethylamino)methyl>-2-furanyl>methyl>thio>ethylamino
            Analogs of Ranitidine
 Abstract:
            A series of
            N-aryl-2-<<<5-<(dimethylamino)methyl>-2-furanyl>methyl>thio>ethylamino
            analogs of the H2-antagonist, ranitidine, was synthesized and the abilities of
            the compounds to alleviate the cholinergic deficit characteristic of
            Alzheimer's disease evaluated.The compounds were initially tested for their
            ability to inhibit human erythrocyte acetylcholinesterase activity in
            vitro.Selected compounds were further evaluated for butyrylcholinesterase
            inhibition, M1 and M2 cholinergic receptor binding, potentiation of ileal
            contractions, and the ability to elevate brain acetylcholine levels in mice.The
            analogs were compared to tetrahydroaminoacridine and to a recently
            reported series of bis-<<(dimethylamino)methyl>furans>.The
            N-aryl-2-<<<5-(dimethylamino)methyl>-2-furanyl>methyl>thio>ethylamine
            derivatives were generally comparable to tetrahydroaminoacridine and the
            bis<<(dimethylamino)methyl>furans> in acetylcholinesterase inhibition,
            M1/M2 receptor binding, and the potentiation of ileal contractions, while
            being more potent inhibitors of acetylcholinesterase than
            butyrylcholinesterase.The 4-nitro-3-pyridazinyl analog, 26, was notable in
            demonstrating a potent and selective binding to the M2 receptor, with an M2
            IC50/M1 IC50 of 0.060.Compounds in which the substituents on the
            dinitro-N-aryl moiety were relatively small were the best at inhibiting
            acetylcholinesterase in vitro.The
            N-aryl-2-<<<5-<(dimethylamino)methyl>-2-furanyl>methyl>thio>ethylamines
            in general, and those with small N-aryl substituents in particular, were
            superior to the bis<<(dimethylamino)methyl>furans> in elevating brain ACh
            levels in mice, probably due to enhanced distribution into the CNS.The
            1,5-difluoro--2,4-dinitrophenyl analog, 8, resulted in the largest elevation in
            brain acetylcholine levels, affording a 53percent increase at 88 mg/kg.
 CNR:
            5706099

 Author:
            Jacobson, Kenneth A.; Nikodijevic, Olga; Ji, Xiao-duo; Berkich,
            Deborah A.; Eveleth, David; et al.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 35, 22, 1992, 4143-4149
 Title:
            Synthesis and Biological Activity of N6-(p-Sulfophenyl)alkyl and
            N6-Sulfoalkyl Derivatives of Adenosine: Water-Soluble and
            Peripherally Selective Adenosine Agonists
 Abstract:
            A series of N6-(p-sulfophenyl)alkyl and N6-sulfoalkyl derivatives of
            adenosine was synthesized, revealing that
            N6-(p-sulfophenyl)adenosine (10b) is a moderately potent (Ki vs
            <3H>PIA in rat cortical membranes was 74 nM) and A1-selective
            (120-fold) adenosine agonists, of exceptional aqueous solubility of >
            1.5 g/mL (ca.3M).Compound 10b was very potent in inhibiting synaptic
            potentials in gerbil hippocampal slices with an IC50 of 63 nM.At a dose
            of 0.1 mg/kg ip in rats, 10b inhibited lipolysis (a peripheral A1 effect) by
            85percent after 1 h.This in vivo effect wa s reversed using the
            peripherally selective A1-antagonist
            1,3-dipropyl-8-<p-(carboxyethynyl)phenyl>xanthine (BW1433).The
            same dose of 10b in NIH Swiss mice (ip) was nearly inactive in
            locomotor depression, an effect that has been shown to be centrally
            mediated when elicited by lower doses of other potent adenosine
            agonists, such as N6-cyclohexyladenosine (CHA) (Nikodijevic et
            al.FEBS Lett. 1990, 261, 67).HPLC studies of biodistribution of a
            closely related and less potent homologue,
            N6-<4-(p-sulfophenyl)butyl>adenosine indicated that a 25 mg/kg ip
            dose in mice resulted in a plasma concentration after 30 min of 0.46
            mg/mL and no detectable drug in the brain (detection limit < 0.1percent
            of plasma level).Although 10b at doses > 0.1 mg/kg in mice depressed
            locomotor activity, this depression was unlike the effects of CHA and
            was reversible by BW1433.These data suggest that 10b is a potent
            adenosine agonist in vivo and shows poor CNS penetration.
 CNR:
            5706370

 Author:
            Suzuki, Fumio; Kuroda, Takeshi; Nakasato, Yoshisuke; Manabe,
            Haruhiko; Ohmori, Kenji; et al.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 35, 22, 1992, 4045-4053
 Title:
            New Bronchodilators. 1. 1,5-Substituted
            1H-Imidazo<4,5-c>quinolin-4(5H)ones
 Abstract:
            A series of novel xanthine-based tricyclic heterocycles in
            1H-imidazo<4,5-c>quinolin-4(5H)-ones was designed, synthesized,
            and tested as potential active bronchodilators.Inhibition of the
            Schulz-Dale (SD) reaction-induced contraction in trachea and
            inhibition of antigen inhalation-induced bronchospasm in passively
            sensitized guinea pigs served as primary in vitro and in vivo assays,
            respectively.Simultaneous measurement of acute lethal toxicity
            (minimum lethal dose: MLD, po) in mice allowed determination of a
            safety margin.The bronchodilatory activity of these heterocycles was
            considerably varied with the nature of substituents at the
            5-position.The most active substituents at the 2- and 5-positions and
            on the aromatic ring were found to be hydrogen, n-butyl, and hydrogen,
            respectively.There was a bulk tolerance for lipophilic substituents at
            the 1-position. 5-Butyl-substituted compounds appeared to be less
            toxic than theophylline on the basis of MLD data.Thus
            5-butyl-1-methyl-1H-imidazo<4,5-c>quinolin-4(5H)-one (10) (IC50
            value of the SD assay = 0.25 mM, MLD >300mg/kg) was selected for
            further studies.Compound 10 (KF 15570) reduced bronchoconstriction
            produced by antigen (Konzett-Roessler preparation in anesthetized
            guinea pigs, ED50 = 0.42 mg/kg, iv) more effectively than
            aminophylline (ethylenediamine salt of theophylline, ED50 = 7.8
            mg/kg, iv) but had fewer side effects on the heart and CNS than
            theophylline.Compound 10 and its derivatives showed weak
            adenosine antagonism and phosphodiesterase (PDE) inhibition which
            could not account for their potent bronchodilation.Although their
            precise mechanism of action remains unclear, this series of novel
            tricyclic heterocycles represents a new class of bronchodilator.
 CNR:
            5707329

 Author:
            Mule, Antonio; Pirisino, Gerolamo; Moretti, Mario D.; Sparatore, Fabio;
            Dimich, Peppina Manca; et al.
 Reference:
            Journal, FRMCE8, Farmaco, EN, 47, 9, 1992, 1161-1172
 Title:
            Cyclopentenyl Ethylamines Active on CNS
 Abstract:
            Two new cyclopentenylethylamines were prepared and were
            submitted to a pharmacological screening together with some others
            previously described and now reprepared.All compounds exhibited
            different degrees of depressive activity on CNS and good analgesic
            activity.Compound 5, bearing a phenyl group on the carbon atom to
            which the amino group is connected, appears rather interesting being
            the most active as analgesic and the least toxic.Compounds 2 and 3
            are able to antagonize in a certain degree lethal doses of
            physostigmine and also, respectively, of pentylenetetrazole and
            strychnine.
 CNR:
            5707333

 Author:
            Wuensch, Bernhard; Zott, Matthias; Hoefner, Georg
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), GE, 325, 11, 1992,
            733-740
 Title:
            Synthesis of Enantiomerically Pure
            6,10-Epoxybenzocycloocten-7-amines with CNS-Activity
 Abstract:
            In an oxa-Pictet-Spengler reaction the methyl (S)-phenyllactate 6 and
            methyl levulinate (7a) are condensed to the 2-benzopyrans cis-8a and
            trans-8a, which react with CH3I to yield the dimethyl ethers cis-9a and
            trans-9a.Cis-9a and trans-9a can be separated by medium pressure
            liquid chromatography.In the subsequent Dieckmann-cyclisation
            cis-9a is transformed to the laevorotatory b-ketoester (-)-10a, while the
            dextrorotatory enantiomer (+)-10a is obtained from trans-9a after
            C-3-epimerisation.With Eu(hfc)3 the ketone (-)-11, prepared by
            saponification and decarboxylation of (-)-10a, proves to be
            enantiomerically pure.By reductive amination, ketone (-)-11 is
            transformed to the amines (-)-12a and (-)-12b.Symptoms typical for
            central damping are caused after i.p. application of (-)-12a and (-)-12b
            to mice.In the mouse writhing-test (-)-12a*HCl affords an ED50 - value
            of 7.0 mg/kg, comparable with the ED50-value of tramadol.
 CNR:
            5709174

 Author:
            Neu, I. S.; Wildfeuer, A.; Mallinger, J.; Mehler, L.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 42, 9, 1992, 1083-1086
 Title:
            Suppression of Experimental Autoimmune Encephalomyelitis by a New Specific
            Inhibitor of Leucotriene Biosynthesis
 Abstract:
            The actions of the specific inhibitor of leucotriene synthesis,
            3-<1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl>-2,2-dimethylpropanoic
            acid (L-663, 536, CAS 118414-82-7) were investigated in groups of guinea pigs
            that had been given both low and high doses of the encephalitogenic stimulant to
            induce experimental autoimmune encephalomyolitis (EAE).After daily
            intraperitoneal application over a period of 2 to 3 weeks the substance L-663,
            536 (5 mg/kg) largely suppressed the clinical symptoms of EAE in some of the
            animals.The difference in the clinical symptoms between those animals that had
            been treated with L-663, 536 and those that had not was observed primarily in
            the experiment with a high encephalitogenic dose.The onset of progressive
            paralysis of the hind limbs that was observed in approximately 80percent of the
            control animals only occurred in 40percent of the guinea pigs that were treated
            with L-663, 536.No paresis at all was observed in about 25percent of the treated
            animals.In both laboratory animals studies the CNS inflammatory infiltrates were
            significantly less extensive in the treated animals than in the respective control
            groups.The release of leucotrienes B4 and C4 by circulating neutrophil
            granulocytes in guinea pigs under treatment with L-663, 536 was also
            significantly reduced - in contrast to the untreated control animals.On the basis of
            the present results, it may be assumed that the L-663, 536-induced suppression
            of EAE in guinea pigs is attributable to the inhibition of leucitriene biosynthesis.
            Key words: Autoimmune encephalomyelitis, experimental; CAS 118414-82-7;
            3-<1-(4-chlorobenzyl)-3-t-butylthio-5-isopropyl-indol-2-yl>-2,2-dimethylpropanoic
            acid, pharmacology; L-663, 536; multiple sclerosis.
 CNR:
            5709517

 Author:
            Gmeiner, Peter; Sommer, Josef; Hoefner, Georg; Mierau, Joachim
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), EN, 325, 10, 1992,
            649-656
 Title:
            Tricyclic Azaergoline Analogues: Synthesis, Structural Modifications,
            and Pharmacological Studies
 Abstract:
            As an extension of previous investigations on synthesis and dopamine
            autoreceptor activity of bicyclic ergoline analogues the tricyclic
            azaergoline analogues 9a and 9b were synthesized.Furthermore, the
            geometry of the aromatic b-ethylamine moiety of 9a,b was modified by
            stereoselective construction of the cycloheptenyl fused
            pyrazolopyridine derivative 7 and the aminomethyl substituted tricycle
            10.Binding affinity of these compounds at dopamine (DA) receptor
            sites was investigated employing rat striatum homogenate: The
            compounds reveal modest to weak, but selective binding to a
            dopamine D-2 receptor when it is labelled with the DA-autoreceptor
            agonist <(3)H>-SND 919.In vivo studies with mice showed that 7, 9a,b,
            and 10 affect their CNS activity.
 CNR:
            5710643

 Author:
            Lazzaroni, M.; Cattalini, C.; Massetto, N.; Poli, A.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., GE, 42, 11A, 1992, 1410-1413
 Title:
            Dihydroergocristine in Organic Brain Syndrome / Placebo-controlled
            multicenter clinical double-blind study in 240 patients
 Abstract:
            The aim of this 3-month study was to assess the activity of
            dihydroergocristine (DHEC, CAS 17479-15-5) on organic brain
            syndrome.DHEC is an ergot alkaloid derivative with a dopaminergic
            activity on the central nervous system (CNS).It improves cerebral
            metabolism and increases the bioelectric potential in the cerebral
            cortex.The randomized double-blind trial versus placebo involved 240
            outpatients (138 females and 102 males, mean age 68 years) recruited
            in 6 hospitals.Subjects with Hachinski Ischemic Score > 6 and Mini
            Mental State < 22 were excluded.Patients were randomly divided into
            4 groups of 60 subjects each to receive either one 6-mg DHEC oral
            vial or placebo vial, or one 6-mg DHEC tablet or placebo tablet once
            daily for 3 months.Neuropsychological tests were performed at
            baseline, and then after 45 and 90 days of treatment.The statistical
            analysis of results showed a significant difference (p < 0.01 ) between
            DHEC and placebo groups with regard to the following tests: "Scale of
            Clinical Assessment for Geriatrics (SCAG), Digit Symbol, Digit Span,
            Toulouse-Pieron, Hamilton Depression Rating Scale and Rey's
            Words".The amelioration of clinical symptoms pointed out the
            equivalence of DHEC oral vials and tablets.The drug was well
            tolerated.It is concluded that DHEC is an effective and safe drug in the
            treatment of organic brain syndrome.Key words: CAS 17479-19-5 *
            Decme<*> intens * Dihydroergocristine, clinical studies * Organic brain
            syndrome
 CNR:
            5711357

 Author:
            Constanzo, Annarella; Bruni, Fabrizio; Guerrini, Gabriella; Selleri,
            Silvia; Aiello, Petra Malmberg; Lamberti, Claudia
 Reference:
            Journal, JHTCAD, J.Heterocycl.Chem., EN, 29, 6, 1992, 1499-1505
 Title:
            Synthesis of Derivatives of
            Pyrazolo<1,5-a>pyrrolo<1,2-c><1,3,6>benzotriazocine, a New Class of
            Compounds with Potential CNS Activity
 Abstract:
            The synthesis of derivatives of
            pyrazolo<1,5-a>pyrrolo<1,2-c><1,3,6>benzotriazocine was obtained by
            the reaction of arylaldehydes with some
            1-(2-aminophenyl)-5-(pyrrol-1-yl)pyrazoles, as
            hydrochlorides.Characterization of this new class of compounds was
            effected with ir, pmr and 13C nmr spectral date.
 CNR:
            5713340

 Author:
            Selleri, S; Bruni, F; Costanzo, A; Guerrini, G; Aiello, P Malmberg; et al.
 Reference:
            Journal, EJMCA5, Eur.J.Med.Chem.Chim.Ther., EN, 27, 9, 1992,
            985-990
 Title:
            Synthesis and preliminary evaluation of
            pyrazolo<1,5-a>pyrido<3,4-e>pyrimidin-6(7H)-ones and related
            compounds, as benzodiazepine receptor ligands and anticonvulsant
            agents
 Abstract:
            pyrazolo<1,5-a>pyrido<3,4-e>pyrimidin-6(7H)-ones /
            ethyl-7-methylpyrazolo<1,5-a>pyrimidin-6-carboxylates / 2 or
            3-substituted
            6-methylpyrazolo<1,5-a>pyrido<3,4-e>pyrimidin-N7-oxide /
            diethyl-7-methylpyrazolo<1,5-a>pyrimidin-3,6-dicarboxylates /
            synthesis / CNS activity / flunitrazepam binding study
 CNR:
            5714620

 Author:
            Hazai, L.; Deak, Gy.; Toth, G.; Sohar, P.; Tamas, J.; Gyoergi, L.
 Reference:
            Journal, ACHUDC, Acta Chim.Hung., EN, 129, 2, 1992, 269-275
 Title:
            CONDENSED HETEROCYCLIC LACTAMS, II. SYNTHESIS OF NEW
            4-ARYLQUINOLIN-2(1H)-ONE DERIVATIVES
 Abstract:
            Catalytic hydrogenation of the nitro group of
            4-(4-nitrophenyl)quinolin-2(1H)-one (1) gave, without saturation of the
            C-3 - C-4 double bond, a new representative of
            4-aryl-quinolin-2(1H)-ones: the 4-(4-aminophenyl) derivative 3.The use
            of this compound as a starting material made possible the syntheses
            of potentially CNS active 4-alkylaminoacylamino-substituted
            4-arylquinolin-2(1H)-ones (6a-d) and related compounds (6e-j).
 CNR:
            5754224

 Author:
            Kumar, Ashok; Ner, D H; Dike, Suneel
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 31, 12, 1992, 803-809
 Title:
            A novel chemoenzymatic enantioselective synthesis of some clinically
            effective CNS drugs and related compounds
 Abstract:
            We have demonstrated in this study a novel route for the synthesis of
            benzothiopyran and benzothiazepin ring systems along with the
            synthesis of optically pure, clinically effective drugs tomoxetine,
            fluoxetine and thiazesim.
 CNR:
            5811730

 Author:
            Ohshima, Etsuo; Otaki, Shizuo; Sato, Hideyuki; Kumazawa, Toshiaki; Obase,
            Hiroyuki; et al.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 35, 11, 1992, 2074-2084
 Title:
            Synthesis and Antiallergic Activity of
            11-(Aminoalkylidene)-6,11-dihydrodibenz<b,e>oxepin Derivatives
 Abstract:
            A new series of 11-substituted 6,11-dihydrodibenz<b,e>oxepin-2-carboxylic acid
            derivatives was synthesized and demonstrated to be orally active antiallergic
            agents.These compounds are structurally related to 1 (KW-4994), which we had
            reported previously to be a new antiallergic agents.Most compounds synthesized
            exhibited potent inhibitory effects on 48-h homogolous passive cutaneous
            anaphylaxis (PCA) in rats and on IgG1-mediated bronchoconstriction in guinea
            pigs.Additionally, compounds possessing a terminal carboxyl group at the
            2-position of the dibenz<b,e>oxepin ring system exhibited inhibitory effects on
            specific <3H>pyrilamine binding to guinea pig cerebellum histamine H1
            receptors, whereas these demonstrated negligible effects on specific <3H>QNB
            binding to rat striatum muscarinic acetylcholine M1 receptors.Structure-activity
            relationship studies revealed that the following key elements were required for
            enhanced antiallergic activities: (1) a 3-(dimethylamino)propylidene group as the
            side chain at the 11-position, (2) a terminal carboxyl moiety at the 2-position, and
            (3) a dibenzoxepin ring system.Among the compounds synthesized,
            (Z)-11-<3-(dimethylamino)propylidene>-6,11-dihydrodibenz<b,e>oxepin-2-acetic
            acid hydrochloride (16) was selected for further evaluation.It had an ED50 value
            of 0.049 mg/kg po in the PCA test in rats and an ID50 value of 0.030 mg/kg po in
            inhibiting anaphylactic bronchoconstriction in guinea pigs.Furthermore, it had a
            Ki value of 16 +/- 0.35 nM for the histamine H1 receptor, while it exhibited
            negligible CNS side effects up to a dose of 600 mg/kg po.Compound 16 is now
            under clinical evaluation as KW-4679.
 CNR:
            5856366

 Author:
            Roig, M. G.; Bello, F.; Burguillo, F. J.; Cachaza, J. M.; Kennedy, J. F.
 Reference:
            Journal, JPMSAE, J.Pharm.Sci., EN, 80, 3, 1991, 267-270
 Title:
            In Vitro Interaction between Psychotropic Drugs and Alcohol
            Dehydrogenase Activity
 Abstract:
            A series of CNS-stimulating and-depressant drugs have been studied
            for their in vitro interaction with horse liver alcohol dehydrogenase
            (ADH) activity.The depressant drugs studied included barbital,
            phenobarbital, thiopental, nitrazepam, chlorpromazine, sulpiride,
            clomethiazole, Li2CO3, diazepam, phenytoin, ethosuximide,
            morphine, and codeine.The stimulant drugs were theopylline, caffeine,
            amphetamine, imipramine, chlorimipramine, amitriptyline, and
            tranylcypromine.The results were as follows.First, ADH activity was
            inhibited by the action of chlorpromazine, tranylcypromine, imipramine,
            chlorimipramine, amitriptyline, sulpiride, amphetamine, codeine,
            ethosuximide, morphine, clomethiazole, nitrazepam, Li2CO3,
            theophylline, and phenobarbital, in descending order of inhibitory
            effect.Second, inhibition followed by activation of ADH activity was
            observed for imipramine and chlorimipramine.Third, activation of ADH
            activity was observed for phenytoin.Finally, the following drugs were
            not seen to exert any effect on ADH activity: barbital, thiopental,
            diazepam, and caffeine.
 CNR:
            5525631

 Author:
            Soine, William H.; Soine, Phyllis J.; England, Terry M.; Ferkany, John
            W.; Agriesti, Bruce E.
 Reference:
            Journal, JPMSAE, J.Pharm.Sci., EN, 80, 2, 1991, 99-103
 Title:
            Identification of Phenobarbital N-Glucosides as Urinary Metabolites of
            Phenobarbital in Mice
 Abstract:
            Previously, the N-glucosylation of phenobarbital had been observed
            only in humans.The results of a species screen (mouse, rat, guinea
            pig, rabbit, cat, dog, pig, and monkey) found that only mice excreted
            the N-glucosides of phenobarbital in urine after ip administration of
            sodium phenobarbital.The major diastereomer excreted by the mouse
            had the R configuration at the C-5 position of the barbiturate ring.The
            N-glucoside metabolites accounted for a small percentage of the dose
            (ca. 0.5percent).Following ip dosing of the mouse with the
            phenobarbital N-glucosides, free phenobarbital could be detected in
            the urine.Upon ip or intercerebroventricular (icv) injection of the
            phenobarbital N-glucosides, minimal CNS activity was observed in the
            mouse.
 CNR:
            5526358

 Author:
            Bowler, Andrew N.; Doyle, Paul M.; Young, Douglas W.
 Reference:
            Journal, JCCCAT, J.Chem.Soc.Chem.Commun., EN, 5, 1991,
            314-316
 Title:
            Synthesis of Potential Agonists and Antagonists for Central Glutamate
            Receptors by a Novel 'Ring Switching' Process
 Abstract:
            Heterocyclic derivatives 6 of (S)-glutamic acid, which are structurally
            related to key central nervous system (CNS) glutamate receptor
            agonists,are prepared from the aldehyde 9 using a novel reaction in
            which the pyroglutamate ring is cleaved in concert with formation of the
            new heterocyclic ring.
 CNR:
            5528376

 Author:
            Chumpradit, Sumalee; Kung, Mei-Pung; Billings, Jeffrey J.; Kung, Hank F.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 34, 3, 1991, 877-883
 Title:
            Synthesis and Resolution of
            (+/-)-7-Chloro-8-hydroxy-1-(3'-iodophenyl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
            (TISCH): A High Affinity and Selective Iodinated Ligand for CNS D1 Dopamine Receptor
 Abstract:
            The synthesis and resolution of
            (+/-)-7-chloro-8-hydroxy-1-(3'-iodophenyl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine,
            (+/-)-TISCH (8) has been achieved by resolution of intermediate 4, the O-methoxyl,
            3'-bromo derivative, as the diastereomeric camphor sulfonate salt.The final products,
            R-(+)-8 and S-(-)-8, were prepared by treatment of R-(+)- or S-(-)-7, the 3'-tributyltin
            intermediates, with iodine in chloroform, followed by O-demethylation.By using HPLC
            with a chiral column, the optical purity (>99percent) of the intermediates and the final
            compounds was determined.Radioiodination was achieved by an iodo-destannylation
            reaction with sodium <125I>iodide and hydrogen peroxide.As expected, the
            R-(+)-<125I>-8 (the active isomer) displayed high affinity and selectivity to the CNS D-1
            receptor in rat striatum tissue preparation (Kd = 0.205 nM).The rank order of potency was
            as follows: SCH-23390 (1a) > (+/-)-8 > (+)-butaclamol > spiperone, WB4101 > dopamine,
            5-HT.After an iv injection, the R-(+)-<125I>-8 penetrated the blood-brain barrier with ease
            and displayed specific regional distribution corresponding to the D-1 receptor density,
            while the S-(-)-<125I>-8 showed no specific uptake.The data suggest that the ligand may
            be useful as a pharmacological tool for characterizing the D-1 dopamine receptor.When
            labeled with I-123, this ligand is a potential agent for in vivo imaging of CNS D-1
            dopamine receptor.
 CNR:
            5528636

 Author:
            Banks, William A.; Kastin, Abba J.
 Reference:
            Journal, JPPMAB, J.Pharm.Pharmacol., EN, 43, 4, 1991, 252-254
 Title:
            Leucine Modulates Peptide Transport System-1 Across the
            Blood-brain Barrier at a Stereospecific Site within the Central Nervous
            System
 Abstract:
            Previous results have shown that leucine injected into a cerebral
            ventricle (i.c.v.) can act as an allosteric regulator of peptide transport
            system-1 (PTS-1), the system that transports
            Tyr-Pro-Leu-Gly-NH2(Tyr-MIF-1) and the enkephalins out of the central
            nervous system (CNS).D-Leucine appeared more potent than
            L-leucine.In the current study, dose-response curves were constructed
            for each compound after both intravenous (i.v.) and i.c.v.
            injection.Based on ED50 values after i.c.v. injection, D-leucine was
            about 200 times more potent than L-leucine in its inhibition of PTS-1,
            thereby confirming stereospecificity of the allosteric site.D- and
            L-Leucine were also more potent when given i.c.v. than when given
            i.v., suggesting that the site is located on the CNS side of the
            blood-brain barrier (BBB).The finding that D-leucine was less potent
            than L-leucine when given i.v. is also consistent with a CNS site of
            action because the L-isomer of leucine has been shown to be
            preferentially transported into the brain.These findings agree with the
            previous suggestion that some of the neurotoxic effects of leucine may
            be mediated through PTS-1 and could help explain how D-amino
            acids can exert opiate-related effects on the CNS.
 CNR:
            5534920

 Author:
            Cox, Jeffrey W.; Sage, G. Patrick; Wynalda, Michael A.; Ulrich, Roger
            G.; Larson, Philip G.; Su, Ching C.
 Reference:
            Journal, JPMSAE, J.Pharm.Sci., EN, 80, 4, 1991, 371-375
 Title:
            Plasma Compatibility of Injectables: Comparison of Intravenous
            U-74006F, a 21-Aminosteroid Antioxidant, with Dilantin Brand of
            Parenteral Phenytoin
 Abstract:
            The 21-aminosteroid antioxidant U-74006F (1) is being developed as
            an iv injectable agent for the treatment of human CNS trauma and
            ischemia.Because of its poor water solubility, the plasma compatibility
            of the parenteral formulation of 1 was evaluated using three models: (I)
            static solubility, (II) aggregometric, and (III) dynamic flow.The flow
            model was designed to mimic an iv infusion into the human
            antecubital vein, which was assumed to have plasma flow of 10
            mL/min.Dilantin (phenytoin, the positive control, produced a precipitate
            in all three models from a 10percent (v/v) mixture with human plasma,
            which approximates the in vivo ratio when the drug is infused at the
            recommended rate of 1 mL/min.Approximately 39percent of the
            phenytoin dose in the flow model was retained on a downstream 3-mm
            filter as crystals.In comparison, the parenteral formulation of 1
            produced minimal precipitate in models I and II from 40percent
            mixtures with plasma, but higher percentages produced unstable
            suspensions with time-dependent precipitation.The percentage of the
            dose of the parenteral formulation of 1 retained on the filter in the flow
            model was 0.5percent or less at infusion rates as high as 10 mL/min
            and 3percent at 19 mL/min.At the 10-mL/min infusion rate, the mass of
            1 retained on the filter per minute was <1percent of the mass of
            phenytoin retained at the 1-mL/min infusion rate for Dilantin.The
            acceptable plasma compatibility of the parenteral formulation of 1
            appears to be related to the solubilizing effects of plasma protein
            binding and pH suppression by the citric acid vehicle.
 CNR:
            5534950

 Author:
            Bishop, John E.; Mathis, Chester A.; Gerdes, John M.; Whitney, John M.;
            Eaton, Allison M.; Mailman, Richard B.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 34, 5, 1991, 1612-1624
 Title:
            Synthesis and in Vitro Evaluation of
            2,3-Dimethoxy-5-(fluoroalkyl)-Substituted Benzamides: High-Affinity
            Ligands for CNS Dopamine D2 Receptors
 Abstract:
            A number of
            2,3-dimethoxy-5-(fluoroalkyl)-N-<(1-ethyl-2-pyrrolidinyl)methyl>benzamides
            (with or without a 6-hydroxy group) were synthesized and evaluated as
            dopamine D2 receptor ligands.The parent acids were synthesized via the
            Claisen rearrangement of the appropriate O-allyl ethers, which were derived
            from o-vanillic acid or 2,3-dimethoxysalicylic acid.A decrease in reactivity
            was found to be characteristic of pentasubstituted benzoates, and difficulties
            were encountered with the introduction of fluorine onto the ethyl side
            chains.The (fluoroethyl)- and (fluoropropyl)salicylamides were 5 times more
            potent than the corresponding benzamides in inhibiting <3H>spiperone
            binding to the D2 receptor.These (fluoroalkyl)salicylamides are of potent
            value for in vivo positron emission tomography (PET) studies upon the
            basis of their relatively selective, high potency binding affinity for the D2
            receptor.
 CNR:
            5536021

 Author:
            Williams, P. D.; Calligaro, D. O.; Colbert, W. E.; Helton, D. R.; Shetler,
            T.; et al.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 41, 3, 1991, 189-195
 Title:
            General Pharmacology of a New Potent 5-Hydroxytryptamine
            Antagonist
 Abstract:
            The potential of the investigational 5-hydroxytryptamine (5HT3)
            antagonist, LY277359, to alter cardiovascular, central nervous system
            (CNS), smooth muscle, and gastrointestinal functions at multiples of
            pharmacologically active doses, was examined to provide a profile of
            possible secondary pharmacological effects.In the anesthetized dog,
            significant cardiovascular effects were observed at doses 100-1000
            and 4-15 times those found to be pharmacologically active at 5HT3
            receptors in vivo in rats and dogs, respectively.These effects were
            limited to decreased heart rate (approximately 20percent) at
            intravenous doses of 1.75 and 3.5 mg/kg and prolonged Q-Tc intervals
            (approximately 20 to 50percent) at doses of 0.438 to 3.5 mg/kg.At an
            oral dose of 135 mg/kg (representing 1500-4500 times the
            pharmacologically active dose in rats), LY277359 induced hypoactive
            behavior and reduced body temperature in mice.Seizure activity was
            potentiated at high oral doses of LY277359 (45 and 135 mg/kg).A
            single oral dose of 135 mg/kg increased hexobarbital-induced sleep
            time.In smooth and cardiac muscle tissue studies in vitro, LY277359
            was essentially inactive: it did not alter contractile activity or receptor
            function of the guinea pig ileum, rat vas deferens, rat uterus, or guinea
            pig atria at concentrations of 1E-5 to 1E-10 mol/l.At a concentration
            50,000 times the 5HT3 antagonistic level in vitro (1E-4 mol/l),
            LY277359 inhibited the response of the ileum to field stimulation,
            acetylcholine and angiotensin I, and suppressed the rate of the
            spontaneously beating guinea pig atria in a noncompetitive
            manner.When gastrointestinal motility was examined in the mouse,
            orally administered LY277359 produced a slight, but significant,
            dose-dependent decrease in charcoal meal transit distance at doses of
            0.01 to 100 mg/kg.Based upon the results of these studies, LY277359
            exhibits a high degree of pharmacological selectivity for 5HT3
            receptors, and possesses a limited potential for functional side effects.
 CNR:
            5537166

 Author:
            Ergenc, N.; Bueyuektimkin, S.; Capan, G.; Baktir, G.; Rollas, S.
 Reference:
            Journal, PHARAT, Pharmazie, EN, 46, 4, 1991, 290-291
 Title:
            Quinazolinones. 19. Communication: Synthesis and evaluation of some CNS
            depressant properties of
            3-(2-<5-aryl-1,3,4-oxadiazole-2-yl)amino>acetamido)-2-methyl-4(3H)-quinazolinones
 Abstract:
 CNR:
            5538076

 Author:
            Ammon, H. P. T.
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), EN, 324, 5, 1991, 261-267
 Title:
            Biochemical Mechanism of Caffeine Tolerance
 Abstract:
            Most of the biological actions of caffeine are possibly mediated through
            its antagonistic effects to adenosine.Adenosine activates an inhibitory
            GTP-binding protein (Gi).One of the physiological actions of Gi is the
            inhibition of cAMP formation.Caffeine overcomes this action thus
            leading to elevation of cAMP.Firing of neurons and the release of
            neurotransmitters is also inhibited by adenosine.Caffeine overcomes
            this effect, thus producing increased CNS-activity.During long term
            administration of caffeine many functions of the organism develope
            tolerance including cardiovascular and central nervous
            systems.Present evidence suggests that caffeine tolerance following
            continuous severe coffee ingestion is the response of the body against
            caffeine through the upregulation of adenosine receptors.
 CNR:
            5540297

 Author:
            Oshiro, Yasuo; Sakurai, Youji; Tanaka, Tatsuyoshi; Ueda, Hiraki;
            Kikuchi, Tetsuro; Tottori, Katura
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 34, 7, 1991, 2004-2013
 Title:
            Novel Cerebroprotective Agents with Central Nervous System
            Stimulating Activity. 1. Synthesis and Pharmacology of
            1-Amino-7-hydroxyindan Derivatives
 Abstract:
            To developed a novel cerebroprotective agent with central nervous
            system (CNS) stimulating activity, a series of 1-amino-7-hydroxyindan
            derivatives was synthesized, and their effects on the survival time of
            mice under hypoxic conditions were tested.CNS-stimulating activity
            was also evaluated by examining the promotional effect on the
            recovery from cerebral concussion induced coma in mice.Several
            compounds prolonged the survival time of mice in hypoxic conditions
            at a dose of 30 mg/kg (sc or ip) and 100 mg/kg (po).They also
            exhibited the promotional effects on recovery from coma at a dose of
            100 mg/kg po.The three most potent compounds in both tests,
            1-amino-7-hydroxy-6-(1-methylpropyl)indan (20),
            1-amino-7-hydroxy-4,6-dimethyl-2-phenylindan (30), and
            1-amino-7-hydroxy,2,2,4,6-tetramethylindan (35) were selected for
            further investigations.Structure-activity relationships were also
            discussed.
 CNR:
            5582101

 Author:
            Oshiro, Yasuo; Sakurai, Youji; Tanaka, Tatsuyoshi; Kikuchi, Tetsuro; Hirose, Tsuyoshi;
            Tottori, Katsura
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 34, 7, 1991, 2014-2023
 Title:
            Novel Cerebroprotective Agents with Central Nervous System Stimulating Activity. 2.
            Synthesis and Pharmacology of the 1-(Acylamino)-7-hydroxyindan Derivatives
 Abstract:
            In a continuous search for a novel cerebroprotective drug with a central nervous system
            (CNS) stimulating activity, a series of 1-(acylamino)-7-hydroxyindan derivatives has been
            synthesized and tested for its dual activities.The cerebroprotective activities of the
            compounds in this series were evaluated in terms of their effect on the survival of mice in
            hypoxic conditions (210 mm Hg), and their CNS stimulating activities were examined by
            evaluating their promotional effects on the recovery from coma induced by cerebral
            concussion in mice.Several compounds prolonged the survival of mice in the hypoxic
            conditions at a dose of 30 mg/kg po.Four compounds in this series showed the
            CNS-stimulating effect at the same dose.Among them,
            7-hydroxy-1-<<4-(3-methoxyphenyl)-1-piperazinyl>acetyl>amino>-2,2,4,6-tetramethylindan
            (18, OPC-14117), which was active in the two tests with no side effect up to 500 mg/kg po
            daily for 2 weeks of administration to rats, was selected for preclinical investigations.
 CNR:
            5582102

 Author:
            Eiden, Fritz; Denk, Felix
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), GE, 324, 6, 1991,
            353-354
 Title:
            Synthesis and CNS-Activity of Pyran Derivatives:
            6,8-Dioxabicyclo<3,2,1>octanes
 Abstract:
            The amino nitriles 4a,b and 5a,b, prepared from
            (1S,5R)-6,8-dioxabicyclo<3,2,1>octan-4-one (2), react with
            phenylmagnesium bromide to afford the diastereomeric
            4-amino-4-phenyl derivatives 7a,b and 8a,b, respectively.The
            diastereomeric piperidine derivatives 7b and 8b show different
            CNS-activity.
 CNR:
            5587179

 Author:
            Lien, Eric J.; Gao, Hua; Prabhakar, Hassan
 Reference:
            Journal, JPMSAE, J.Pharm.Sci., EN, 80, 6, 1991, 517-521
 Title:
            Physical Factors Contributing to the Partition Coefficient and Retention
            Time of 2',3'-Dideoxynucleoside Analogues
 Abstract:
            Acquired immunodeficiency syndrome (AIDS) is an
            immunosuppresive disease characterized by an immune impairment
            and a high susceptibility to unusual forms of certain neoplasms.Since
            the brain is an important site of the infection, it is necessary to explore
            new classes of drugs that have ability to penetrate across the
            blood-brain barrier, and the potency to suppress viral replication within
            the central nervous system (CNS).Therefore, the ability to predicate the
            lipophilicity of the potent anti-AIDS drugs may provide useful
            information about the potential of the drugsto enter CNC.In this paper,
            the correlations of log P (octanol-buffer partition coefficient) and log tR
            (retention time in HPLC; Rt was used by Balzarini et al.) with some
            physical constants like log MW (molecular weight), hydrogen bond
            forming ability (HB) of the substituents, and the substituent group
            dipole moments (m) are analyzed.Good correlations of log P and log tR
            with log MW, HB, and m have been obtained.
 CNR:
            5588042

 Author:
            Veng-Pedersen, Peter; Mandema, Jaap W.; Danhof, Meindert
 Reference:
            Journal, JPMSAE, J.Pharm.Sci., EN, 80, 9, 1991, 881-886
 Title:
            Biophase Equilibration Times
 Abstract:
            Various methods for describing how quickly a drug equilibrates at the
            biophase are proposed.The biophase equilibration time (BET) is the
            time it takes the biophase drug level to reach a given percentage (p) of
            its predicted steady state in a drug administration that leads to a
            steady-state condition.The time to reach biophase equilibrium may be
            defined as the BET value for p = 95, and the 50percent biophase
            equilibration time is obtained when p = 50.Biophase equilibration
            profiles (BEPs), obtained by plotting p versus BET, give a dynamic
            representation of the approach to equilibrium and may serve as an
            indicator of the rate of drug delivery to the biophase.A
            pharmacodynamic system analysis method is proposed to determine
            BETs and BEPs from the biophase conduction function.The approach
            is demonstrated using pharmacodynamic data from the CNS effect of
            amobarbital evaluated by an aperiodic analysis of EEG recordings.The
            relevance of the BET and/or BEP principles in optimal
            computer-controlled drug infusion, drug design, and evaluation of
            targeted drug delivery is discussed.Both vascular and extravascular
            drug administrations are considered in the analysis.
 CNR:
            5588514

 Author:
            Colado, M. I.; Alfaro, M. J.; Lopez, F.; Del Val, V.; Martin, M. I.
 Reference:
            Journal, JPPMAB, J.Pharm.Pharmacol., EN, 43, 9, 1991, 662-664
 Title:
            The effect of dihydropyridine calcium channel agents on 5-HT
            matabolism in the CNS of the rat
 Abstract:
            The effects of dihydropyridines on the levels of 5-hydroxytryptamine
            (5-HT) and 5-hydroxy-3-indole acetic acid (5-HIAA) in the spinal cord
            and various brain regions of the rat have been studied.Nimodipine,
            nitrendipine and nifedipine (10 mg kg-1), nisoldipine (5 mg kg-1), and
            BAY K 8644 (0.2 and 2 mg kg-1) were administered i.p. 1 h before
            killing.The administration of nifedipine and nitrendipine increased
            5-HT turnover in all of the areas studied except for the spinal
            cord.Nisoldipine increased 5-HT turnover in midbrain, hippocampus
            and cortex, while the effect of nimodipine was restricted to
            midbrain.BAY K8644 at 2 mg kg-1 produced the same effects as
            nifedipine and nitredipine; however, at low doses (0.2 mg kg-1), this
            compound increased 5-HT turnover only in midbrain and medulla
            oblongata.These results indicate that both dihydropyridine calcium
            channel agonist and atagonists are able to activate the 5-HT-ergic
            system in the central nervous system of the rat in-vivo.Therefore, it
            seems likely that such effects could be due to indirect actions or to
            interactions of the compounds with receptors other than the
            voltage-sensitive calcium channels.
 CNR:
            5588533

 Author:
            Agarwal, Shiv K; Saxena, Anil K; Jain, Padam C; Anand, Nitya; Srimal, R C; Dhawan, Bhola N
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 30, 4, 1991, 413-416
 Title:
            Synthesiis and pharmacological activities of 1-(2,4-disubstituted
            phenoxy)-3-<N1-(N4-arylpiiperazinyl)>propanes and
            1-(4-chlorobenzoyl)-3-substituted-6-methoxy-2-<4-<3-N1-(N4-phenylpiperazinyl)propoxy>phenyl>indoles
 Abstract:
            1-(Substituted phenoxy/thiophenoxy)-3-<N1-(N4-arylpiperazinyl)propanes (2-5),
            1-(2-chloro-4-nitrophenoxy)-3-<N1-<N4-(2-methoxyphenyl)piperazinyl>>propane-2-ol (7) and
            1-(4-chlorobenzoyl)-3-substituted-6-methoxy-2-<4-<3-N1-(N4-phenylpiperazinyl)propoxy>phenyl>indoles
            (8c-e) have been synthesized and evaluated for their CNS, CVS, antiinflammatory, diuretic and PCA
            activities.Compounds 2a and 3a show interesting tranquilizing activity.Hypotensive action is shown by 4
            and 7, while 2e, 3a-b and 8c-e possess antiinflammatory activity.
 CNR:
            5589071

 Author:
            Sastry, C V; Rao, K Srinivasa; Jain, M L
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 30, 5, 1991, 535-536
 Title:
            Synthesis and biological activity of
            2-oxo-1,2,3,3a-tetrahydropyrrolo<3,2-b>-<1,4>benzothiazines
 Abstract:
            A series of oxo-1,2,3,3a-tetrahydropyrrol<3,2-b><1,4>benzothiazines
            (5) has been prepared and tested for their CNS and anti-inflammatory
            activities.
 CNR:
            5589113

 Author:
            Pathak, U S; Singh, S; Padh, J
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 30, 6, 1991, 618-619
 Title:
            Synthesis and biological activities of some 2-(N,N-disubstituted)
            amino-3-phenyl-thieno<2,3-d>pyrimidin-4-(3H)-ones
 Abstract:
            Several
            2-(N,N-disubstituted)amino-3-phenylthieno<2,3-d>pyrimidin-4(3H)-ones
            (2a-j) have been prepared and tested for their analgesic and CNS
            depressant activities.
 CNR:
            5589136

 Author:
            Walker, Judith S.; Levy, Gerhard
 Reference:
            Journal, JPMSAE, J.Pharm.Sci., EN, 80, 10, 1991, 928-930
 Title:
            Kinetics of Drug Action in Disease States. XXXVIII: Effect of Body
            Temperature on the Convulsant Activity of Pentylenetetrazol in Rats
 Abstract:
            The purpose of this investigation was to determine the effect of body
            temperature on the pharmacodynamics (convulsant activity) of
            pentylenetetrazol (PTZ).Rats received an iv infusion of PTZ until the
            onset of maximal seizures, at which time samples of cerebrospinal
            fluid (CSF), brain, and blood (for serum) were obtained for subsequent
            determination of PTZ concentrations by HPLC.The PTZ infusion
            caused a decrease in body temperature of ca. 4 deg C within 20 min
            and onset of seizures in ca. 40 min.Compared with animals whose
            temperature was maintained in the normal range by heating pads, the
            hypothermic rats required significantly larger doses and higher serum,
            brain, and CSF concentrations of PTZ to produce seizures.Other rats
            recelved an injection of brewer's yeast to produce fever.Then, PTZ was
            infused 6, 12, or 24 h later when body temperature was elevated by an
            average of 1.3, 1.1, or 0.4 deg C, respectively.Compared with control
            rats, whose temperature was maintained in the normal range by
            heating pads, moderate hyperthermia had no significant effect on the
            dose and concentration of PTZ required to produce maximum
            seizures.Pentylenetetrazol exemplifies a drug that can produce
            hypothermia which, in tum, reduces the sensitivity of rats to its
            pharmacologic action.Unlike the central nervous system (CNS)
            depressants phenobarbital and ethanol, whose pharmacologic activity
            in rats is enhanced at elevated body temperature, the activity of the
            CNS stimulant PTZ is apparently not altered by fever.
 CNR:
            5589188

 Author:
            Kraemer, Norbert H.; Linde, Hermann F. G.
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), GE, 324, 8, 1991, 527-528
 Title:
            Potentially CNS-active Tricyclic Compounds with Bridged Central Ring, VII:
            9,10-Epithio-1-(w-dimethylaminoalkyl)-4-methoxy-1,2,3,4,4a,9,9a,10-octahydroanthracenes
 Abstract:
 CNR:
            5590722

 Author:
            Amir, Mohammad; Singh, Era
 Reference:
            Journal, PHARAT, Pharmazie, EN, 46, 10, 1991, 705-707
 Title:
            Some new N-substituted a-aryl/alkyl succinimides as possible
            anticonvulsants
 Abstract:
            In view of their expected MAO inhibitory, CNS depressant and
            anticonvulsant properties a number of
            N-(5-alkyl-1,3,4-thiadiazol-2-yl)-a-aryl/alkyl succinimides (1-20) and
            N-(cyclohexyl)-a-aryl/alkyl succinimides (21-25) have been
            synthesized.Some of them when screened for anticonvulsant activity
            against pentetrazole induced seizures in mice at a dose of 80 mg/kg
            were found to be 10 to 50percent active.
 CNR:
            5592103

 Author:
            Kraemer, Norbert H.; Linde, Hermann F. G.
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), EN, 324, 7, 1991, 433-437
 Title:
            Potentially CNS-active Tricyclic Compounds with Bridged Central Ring, VI:
            9,10-Epithio-1-(w-dialkylaminoacyloxy)-4-methoxy-9,10-dihydroanthracene
            Derivatives
 Abstract:
            Monomethylation of the diols 1, 6, and 11 gives compounds 2, 7, and 12
            which were esterified by chloroacetylanhydride to give 3, 8, and 13.The
            target compounds 4, 9, and 14 were obtained by substitution of the chlorine
            atoms by secondary amines.Via the alcoholates of 2 and 7 the further target
            compounds 5 and 10 were synthesized by use of 3-dialkylaminomethyl
            propionates.
 CNR:
            5592381

 Author:
            Bromm, B.; Rundshagen, I.; Scharein, E.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 41, 11, 1991, 1123-1129
 Title:
            Central Analgesic Effects of Acetylsalicylic Acid in Healthy Men
 Abstract:
            Acetylsalicylic acid (CAS 50-78-2) (1000 mg orally) was investigated in
            a non-inflammatory experimental pain model in healthy male
            volunteers, selected for maximal homogeneity.Phasic pain was
            induced by intracutaneously applied electrical pulses of constant
            current.The nociceptive responses measured were, the pain ratings,
            the cerebral potentials and the EEG delta power in response to the
            stimuli.In addition, spontaneous EEG, auditory evoked potentials and
            reaction times were evaluated to determine effects upon the vigilance
            system.The study was performed in a placebo-controlled, double-blind
            repeated measures design.Blood samples were taken to monitor the
            plasma concentrations of the active agents.Acetylsalicylic acid
            produced clear analgesic effects in all pain relevant target
            variables.The effects increased with postmedication time, becoming
            significantly different from placebo 90 min after medication (p <
            0.01).At this time point the pain ratings were reduced by 4 percent, the
            pain related cerebral potentials by 15 percent, and the stimulus
            induced delta power of the EEG by 20 percent.These findings suggest
            a central action of acetylsalicylic acid by attenuation of experimentally
            induced nociceptive activity.No influences could be observed upon
            auditory evoked potentials, spontaneous EEG and reaction times.In
            other words, acetylsalicylic acid did not change vigilance by unspecific
            alternations of the CNS.The plasma concentration of acetylsalicylic
            acid reached mean values of 2.5 +/- 2.4 mg/ml within 25 min after oral
            medication, which remained constant during the entire
            post-medication period of 105 min.In contrast, the concentration of the
            metabolite salicylic acid increased steadily reaching meanvalues of
            32.0 +/- 16.8 mg/ml at the end of the investigated period.Though both,
            the analgesic efficacy and the concentration of salicylate increased
            with postmedication time, no correlations were found between
            individual plasma level and effects. Key words: Acetylsalicylic acid,
            central nervous effects, clinical studies, modulation of EEG
            potentials.CAS 50-78-2.Pain, non-inflammatory
 CNR:
            5594427

 Author:
            Rault, S; Lancelot, JC; Bouyazza, L; Robba, M; Quermonne, MA; et al.
 Reference:
            Journal, EJMCA5, Eur.J.Med.Chem.Chim.Ther., FR, 26, 9, 1991,
            939-946
 Title:
            Synthese et etude preliminaire de l'activite psychotrope d'alkylamino
            et iminopyrrolo<1,2-a>indoles
 Abstract:
            The synthesis of new pyrrolo<1,2-a>indole derivatives is
            described.The habituation test reveals in vivo for some derivatives a
            non amphetaminic CNS stimulant activity. pyrroloindole / synthesis /
            habituation / CNS stimulant / non amphetaminic
 CNR:
            5595120

 Author:
            Kapoor, R P; Sharma, (Km) V P; Singh, Om V; Garg, C P
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 30, 12, 1991, 1152-1155
 Title:
            Synthesis of 3-(2-N-substituted aminothiazol-4-yl)-2-methylchromones
            and 6-(2-N-substituted aminothiazol-4-yl)-2,3-dimethylchromones as
            potential CNS agents
 Abstract:
            The title chromones (IV and VIII) have been synthesized in three steps
            commencing with appropriate a-bromoacylchromones and their
            structures elucidated on the basis of elemental analyses and spectral
            characteristics.A few selected compounds have been screened for
            their CNS, CVS, anti-inflammatory and diuretic activities.
 CNR:
            5596490

 Author:
            Agarwal, Kanchan
 Reference:
            Journal, JICSAH, J.Indian Chem.Soc., EN, 68, 2, 1991, 85-87
 Title:
            Synthesis and Pharmacological Evaluation of some New
            Substituted-1,8-naphthyridines and Substituted-quinazolin-4-ones as
            Hypotensive and CNS Active Agents
 Abstract:
            p-(3-Aroyl-2-phenyl-1,8-naphthyridinyl)methoxyacetylhydrazine on
            reaction with isatin converted into 5 and with
            2-(3'-nitro-4'-chlorophenyl)quinazolin-4-one converted into 10.Both 5
            and 10 on Mannich reaction gave the desired products (7a-j and
            11a-f).The compounds were evaluated for central nervous system
            (CNS) and hypotensive activity.
 CNR:
            5600146

 Author:
            Wuensch, Bernhard; Bauschke, Gerd
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), GE, 324, 11, 1991,
            867-874
 Title:
            Synthesis and Central Effects of 4-Hydroxy-(alkyl)- and
            4-Amino-(alkyl)-Substituted 2,6-Epoxy-3-benzoxocines
 Abstract:
            The tricyclic hemiacetal 1 is transformed with amines to the
            N/O-acetals 3 and 10, with nitromethane to the 4-nitromethyl derivative
            13, and with the Wittig reagents 15a and 15b to the 2-benzopyrans 16
            and 19.Reduction and methylation of 13 yield the tertiary amine 4;
            through three steps the secondary amine 18 and the tertiary amine 5
            are prepared from 16 and 19, respectively.The 1,3-dioxane ring of all
            these 2,6-epoxy-3-benzoxocine derivatives exists in the chair
            conformation with an equatorial C-4 substituent.After application of the
            amines 5, 11c, and 18 mice do not show any symptoms of central
            activity; weak CNS-effects are observed with the alcohols 1 and 2.For
            the tertiary amine 4, which causes considerable central effects
            (Straub-tail-phenomenon, convulsions, etc.), an ED50 of 78 mg/kg is
            determined in the mouse "writhing"-test.
 CNR:
            5602708

 Author:
            Carrara, Maria; Capolongo, Francesca; Cima, Lorenzo; Fabbri,
            Giuseppina; Rampa, Angela; et al.
 Reference:
            Journal, CCCCAK, Collect.Czech.Chem.Commun., EN, 56, 11.1,
            1991, 2402-2405
 Title:
            SEARCH FOR NEW ANALEPTICS: HOMOANALOGUES OF
            DIMEFLINE-TYPE DERIVATIVES
 Abstract:
            The preparation and the pharmacological profile of a selected number
            of homologues at C2 (homoflavones) of dimefline-type analeptics are
            described.The structural modification introduced in I seems to cause a
            remarkable alteration of the CNS stimulating pattern so that the new
            compounds are to be considered as minor analeptics.
 CNR:
            5646879

 Author:
            Moormann, Alan E.; Pitzele, Barnett S.; Jones, P. H.; Gullikson, Gary
            W.; Albin, David; et al.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 33, 2, 1990, 614-626
 Title:
            Potential Antisecretory Antidiarrheals. 2. a2-Adrenergic
            2-<(Aryloxy)alkyl>imidazolines
 Abstract:
            Lofexidine, an a2-agonist, has central hypotensive activity and
            peripheral intestinal antisecretory activity.Analogues were synthetsized
            with increased polarity in an attempt to prevent penetration of the
            blood-brain barrier.The compounds were evaluated in the cholera
            toxin treated ligated jejunum of the rat and in the Ussing chamber with
            a rabbit ileum preparation.Active compounds were determined to be
            a2-adrenergic agonists by yohimbine reversals of their Ussing
            chamber activities.The 2,6-dimethyl derivative of lofexidine, 4a, was as
            active as lofexidine invivo, but derivatives with 2,6-substituents larger
            than ethyl were inactive. (Aryloxy)alkyl derivatives which have an
            imidazoline and a methyl or larger group as part of the alkyl exhibited
            the best antisecretory activity.Compounds with substituents in the para
            position of the phenyl ring were generally inactive.
            3-Amino-2,6-dimethyl derivative 21 was twice as active as 4a.A
            2-methyl substituent is required in the 3-amino series to retain good
            activity. 2-methyl derivative 12a had activity comparable to that of 4a,
            while 6-methyl derivative 12f was inactive.Substituents on the 3-amino
            group did not affect the activity, but substituting a hydroxyl for the
            amino group produced an inactive compounds.Replacing the phenyl
            moiety with a 4-indole resulted in retention of activity, but other
            heterocycles were inactive.Compound 12a was resolved and d isomer
            32 was five times more potent than l isomer 33.The more active
            compounds in the rat cholera toxin assey (RCTA), when evaluated in
            the dog, exhibited antisecretory activity but also exhibited centaral
            nervous system (CNS) effects, sedation and ataxia, at 10 mg/kg, and in
            spontaneouslyhypertensive rats at 50 mg/kg.A measure of polarity, log
            P, was calculated for the (aryloxy)alkyl groups.Regression analysis
            showed no correlation of antisecretory ED50 to the calculated log
            P.The active compounds did not show a separation of the central CNS
            effects from the peripheral antisecretory activity by increasing the
            polarity.
 CNR:
            5500391

 Author:
            Jacob, James N.; Hesse, Gary W.; Shashoua, Victor E.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 33, 2, 1990, 733-736
 Title:
            Synthesis, Brain Uptake, and Pharmacological Properties of a Glyceryl
            Lipid Containing GABA and the GABA-T Inhibitor g-Vinyl-GABA
 Abstract:
            1-O-Linolenoyl-2-O-(4-aminobutyryl)-3-O-(4-vinyl-4-aminobutyryl)glycerol
            (LGV) was synthesized as an example of a prodrug which readily
            penetrates the blood-brain barrier (brain penetration index 97percent +/-
            15percent) and releases two active substances in the central nervous
            system (CNS): GABA (4-aminobutanoic acid) and the GABA
            transaminase inhibitor (GABA-T) of GABA breakdown.In vitro studies
            showed that the compound can inhibit GABA-T after hydrolysis by CNS
            esterases and that it enhanced GABAergic inhibition when applied to rat
            hippocampus slices.In vivo studies indicate that LGV depresses the
            spontaneous locomotor activity of mice.Its activity on a molar basis was
            some 300 times greater than that of g-vinyl-GABA.
 CNR:
            5500769

 Author:
            Dingemanse, Jasper; Hameter, Bart M.; Danhof, Meindert
 Reference:
            Journal, JPMSAE, J.Pharm.Sci., EN, 79, 3, 1990, 207-211
 Title:
            Pharmacodynamics of Tolerance Development to the Anesthetic and
            Anticonvulsant Effects of Phenobarbital in Rats
 Abstract:
            In this study, the potential development of tolerance towards the
            anesthetic and anticonvulsant effects of phenobarbital after chronic
            administration to rats was investigated, differentiating between
            dispositional and functional tolerance.Chronic exposure to
            phenobarbital by daily ip injections of 20 or 100 mg/kg for 14 days
            caused a 30percent increase in clearance within 1 week.No changes
            occurred in the total amounts of phenobarbital and
            para-hydroxyphenobarbital excreted into urine and
            feces.Pharmacodynamic effects were quantitated after 2 weeks of
            treatment.The anesthetic effect was measured by slow iv infusion of
            phenobarbital unit onset of loss of righting reflex (LRR), followed by
            measurement of drug concentrations in serum (both total and free),
            brain, and cerebrospinal fluid (CSF).With a phenobarbital dose of 100
            mg/kg daily, CSF concentrations at the onset of LRR significantly
            increased from 136 +/- 12 to 176 +/- 21 mg/L (p < 0.001), indicating that
            functional tolerance developed for the anestheic effect.Protection of
            phenobarbital against convulsions induced by pentyleneterazol (PTZ),
            as measured by the elevation of the PTZ plasma threshold
            concentration necessary to elicit seizures at the EC50 of phenobarbital,
            was not altered.The discrepancy observed in the development of
            functional adaptation of the CNS demonstrates that different
            mechanisms of action are reflected in the different measures of the
            anesthetic and anticonvulsant effects of phenobarbital that were
            utilized.
 CNR:
            5502256

 Author:
            Murphy, Raymond A.; Kung, Hank F.; Kung, Mei-Ping; Billings, Jeffrey
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 33, 1, 1990, 171-178
 Title:
            Synthesis and Characterization of Iodobenzamide Analogues: Potential D-2
            Dopamine Receptor Imaging Agents
 Abstract:
            (S)-N-<(1-Ethyl-2-pyrrolidinyl)methyl>-2-hydroxy-3-iodo-6-methoxybenzamide
            (<123I>IBZM) is a central nervous system (CNS) D-2 dopamine receptor
            imaging agent.In order to investigate the versatility of this parent structure in
            specific dopamine receptor localization and the potential for developing new
            dopamine receptor imaging agents, a series of new iodinated benzamides
            with fused ring systems, naphthalene (INAP) and benzofuran (IBF), was
            synthesized and radiolabeled, and the in vivo and in vitro biological properties
            were characterized.The best analogue of IBZM is IBF (21).The specific
            binding of <125I>IBF (21) with rat striatal tissue preparation was found to be
            saturable and displayed a Kd of 0.106 +/- 0.015 nM.Competition data of
            various receptor ligands for <125I>IBF (21) binding show the following rank
            order of potentcy: spiperone > IBF (21) > IBZM > (+)-butaclamol >
            (+/-)-ADTN,6,7 > ketanserin > SCH-23390 >> propanolol.The in vivo
            biodistribution results confirm that <125I>IBF (21) concentrated in the striatal
            area after iv injection into rats.The study demonstrates that <125I>IBF (21) is a
            potential agent for imaging CNS D-2 dopamine receptors.
 CNR:
            5502672

 Author:
            Walther, G.; Daniel, H.; Bechtel, W. D.; Brandt, K.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 40, 4, 1990, 440-446
 Title:
            New Tetracyclic Guanidine Derivatives with H1-Antihistaminic
            Properties Chemistry of epinastine
 Abstract:
            A series of new tetracylic guanidines were synthesized by various
            methods.Specific binding of the described compounds to histamine-1
            and histamine-2 receptors was determined.The compound
            3-amino-9,13b-dihydro-1H-dibenz<c,f>imidazo<1.5-a>azepine
            (epinastine, WAL 801, compound IIIa) combines high selectivity with
            high affinity for the H1 receptor and was selected from the compounds
            studied for further pharmacological and clinical
            investigations.Experimentally determined physicochemical
            parameters (pka-value, partition coefficient) and the hydrogen-bonding
            abilityof epinastine are indications that this compound will not easily
            cross the blood-brain barrier.This explains the absence of CNS
            side-effects of epinastine in pharmacological and clinical studies.
 CNR:
            5503853

 Author:
            Buech, H. P.; Omlor, G.; Knabe, J.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., GE, 40, 1, 1990, 32-36
 Title:
            Stereoselektive Unterschiede der zentralnervoes-depressorischen
            Wirkung in einer homologen Reihe von 3-Alkyl-Thalidomid-Analoga
 Abstract:
            The racemates and the enantiomers of the 3-alkyl-thalidomide
            analogues 2a-c were synthesized via the lactams 1a-c.The absolute
            configuration of 1a-c and 2a-c was elucidated, their enantiomeric purity
            established.From racem. 2a 1,3-dimethylthalidomide (3) was
            synthesized.By means of the hexobarbital sleeping time prolongating
            effect in rats it was shown that racem. 2a and 3 were less
            CNS-depressant active than thalidomide; 3 caused a more prolonged
            sleeping time than 2a.Both enantiomers of 2a (i.p. 20 mg/kg) exceeded
            in their sleeping time prolongation action racem 2a (same dose),
            whereby the (S)-enantiomer was to a factor of 1.8 more effective than
            the (R).With both enantiomers of 2a time and dose dependency of the
            effect were investigated. The enantiomers of 2b+c and 1a-c had also a
            prolongating effect on the hexobarbital sleeping time.Independently of
            the alkyl group the (S)-enantiomers were always more active than the
            respective (R)-enantiomers. (S)-1b (200 mg/kg) caused a long lasting
            loss of the righting reflexes as "own effect".Stereoselective differences
            between the enantiomers of 2a and 2b were observed only when a
            dose of 200 mg/kg was applied, whereas the higher activity of the
            (S)-enantiomers of 2c, 1b+c was obtained already with a lower dosage
            range.
 CNR:
            5505990

 Author:
            Compton, David R.; Little, Patrick J.; Martin, Billy R.; Gilman, Jeffery
            W.; Saha, Jayanta K.; et al.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 33, 5, 1990, 1437-1443
 Title:
            Synthesis and Pharmacological Evaluation of Amino, Azido, and
            Nitrogen Mustard Analogues of 10-Substituted Cannabidiol and 11- or
            12-Substituted D8-Tetrahydrocannabinol
 Abstract:
            The synthesis of variety of novel 10-substituted cannabidiol (CBD) and
            11- or 12-substituted D8-tetrahydrocannabinol (D8-THC) analogues
            containing amino, alkylamino, azido, or a N,N-bis(2-chloroethyl)amino
            functional group is described, as well as their pharmacological
            evaluation in mice.These analogues, which possess only a portion of
            the full pharmacological spectrum of activity of D9-THC, indicate that
            cannabinoid-mediated reduction of spontaneous locomotor activity,
            hypothermia, antinociception, and/or catalepsy need not be produced
            simultaneously, possibly suggesting the existence of more than one
            mechanism of action.The 10-substituted CBD analogues 3, 4, and 5
            with an ethylamino, propylamino, or azido functional group,
            respectively, proved to be largely inactive, except for the production of
            central nervous system (CNS) depression concomitant with
            toxicity.Toxicity and CNS depression may be related phenomena in
            these nitrogenous compounds since 12-amino and 12-ethylamino
            anlogues (8 and 11) of D8-THC also proved to be very
            toxic.Antinociceptive and hypothermic responses (without reduction of
            motor activity) were observed at a dose of 10 mg/kg of the
            11-ethylamino analogus (9) of D8-THC, while a dose of 50 mg/kg of the
            nitrogen mustard 11-<N,N-bis(2-chloroethyl)amino>-D8-THC (12) was
            necessary to produce any observable pharmacological effect.When
            selected anlogues were evaluated for antagonistic properties, they
            failed to attenuate the effects of D9-THC.Some nitrogen mustard
            analogues were capable of producing minimal pharmacological
            effects after either peripheral or direct CNS administration; however,
            these analogues also failed to attenuate the effects of D9-THC either
            immediately after administration or 24 - 48 h later.
 CNR:
            5509261

 Author:
            Turski, L.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., GE, 40, 5, 1990, 511-514
 Title:
            N-Methyl-D-aspartat-Rezeptorkomplex. Verschiede Stellen fuer
            Regulation und klinische Konsequenzen
 Abstract:
            Amino acids such as L-glutamate and L-aspartate are major excitatory
            neurotransmitters in the mammalian central nervous system (CNS)
            and potential neurotoxins (excitotoxins), which can destroy central
            neurons by excessive activation of respective receptors.In the last
            three decades evidence has accumulated that excitatory amino acids
            (EAA) are involved in many neurological diseases and that
            pharmacological intervention offers prospects of novel and more
            effective therapies.Three different receptor types for EAA have been
            identified, each being named by the selective agonist to which it is
            preferentially sensitive, i.e.N-methyl-D-aspartate- (NMDA), kainate-
            and quisqualate-receptors.In this rewiev interest is focused primarily
            on the NMDA-receptor, whose structure has been subject of numerous
            electrophysiological and biochemical studies.Today, it is well
            established that the NMDA-receptor-ionophore complex has an
            agonist binding site for glutamate, NMDA and related EAAs which is
            coupled with an ion channel permeable to Na+, K+, Cl- and Ca2+.Four
            other binding sites for glycine, phenylcyclidine, Mg2+ and Zn2+ have
            been identified which can differentially modulate the function of the
            NMDA receptor.An additional polyamine binding site has recently been
            reported.Numerous studies on experimental animals demonstrate that
            modulators of NMDA-mediated neurotransmission may have
            antiepileptic, anxiolytic, muscle-relaxant and memory-enhancing
            effects.Particular interest has gained the possible neuroprotective
            efficacy of NMDA-receptor antagonists in neurological diseases such
            as hypoxia/ischemia, hypoglycemia, epilepsy and chronic
            neurodegenerative disorders (Huntington's, Alzheimer's and
            Parkinson's disease, amyotrophic lateral sclerosis, and AIDS
            encephalopathy).Evidence for the involvement of EAA in the
            pathogenesis of AIDS encephalopathy derives from recent studies
            showing that the CFS levels of quinolate, an endogenous tryptophan
            metabolite and NMDA-receptor agonist, are markedly elevated in
            human immunodeficiency virus (HIV) infection and that the levels
            correlate with the severity of the symptoms of dementia.One should not
            forget that the obvious benefits of clinical trial of NMDA-receptor
            modulators will be accompanied by unwanted side effects such as
            CNS-depression, hallucinations, tolerance development,
            abuse-potential, memory-impairment and even diverse forms of
            neurotoxicity which have not been investigated thoroughly
            yet.However, there is reason to believe that such problems will be
            soon solved to an extent that will allow neurologic patients to benefit
            from the therapeutic use of NMDA-modulators.
 CNR:
            5512500

 Author:
            Costanzo, Annarella; Bruni, Fabrizio; Auzzi, Gabriella; Selleri, Silvia;
            Pecori, Lorenzo Vettori
 Reference:
            Journal, JHTCAD, J.Heterocycl.Chem., EN, 27, 3, 1990, 695-697
 Title:
            Synthesis of CNS Potentially Active Bicyclic and Tricyclic Derivatives
            of Pyrazolo<1,5-a><1,3>diazepines
 Abstract:
            Reaction of 5-ethylamino-3-phenylpyrazole with dicarboxylic acid
            anhydrides in tetrahydrofuran in the presence of
            1,3-dicyclohexylcarbodiimide, afforded bicyclic and tricyclic derivatives
            of pyrazolo<1,5-a><1,3>diazepines.The tricyclic derivatives constitute
            a new class of compounds.Characterisation of these products was
            effected with ir, pmr, and 13C nmr spectral data.
 CNR:
            5513899

 Author:
            Linde, Hermann F. G.; Kraemer, Norbert H.
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), GE, 323, 1990,
            295-299
 Title:
            Synthese von partiell hydrierten 9,10-Epithioanthracenen
 Abstract:
            Potentially CNS-active Tricyclic Compounds with Bridged Central
            Ring, III: Synthesis of Partially Hydrogenated 9,10-Epithioanthracenes
            The synthesis of 9,10-epithio-9,10-dihydroanthracenes is
            presented.Since the direct synthesis from benzo<c>thiophene and
            dehydrobenzene was not possible, benzo<c>thiophene and
            1,4-benzoquinone were reacted by means of Diels-Alder cyclization to
            9,10-epithio-1,4,9,10-tetrahydro-1,4-dioxoanthracene, which we
            intended to convert into 9,10-epithio-9,10-dihydroanthracene after
            intermediate transfer to suitable derivatives.The configurations at the
            connection points 4a and 9a of the partly or completely hydrogenated
            derivatives in one ring were ascertained, as were those in positions 1
            and 4.Sp2-hybridisation of both the C-atoms 4a and 9a resulted in the
            elimination of the sulphur atom.
 CNR:
            5514116

 Author:
            Eiden, Fritz; Wuensch, Bernhard
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), GE, 323, 7, 1990,
            393-399
 Title:
            5,6-Dihydro-6-methoxy-2H-pyrane-3(4H)-one, a Building Block for the
            Syntheses of CNS-Agents
 Abstract:
            The phenyl-pyranyl-piperidin derivative 5, prepared from the title
            compound 2, shows a strong stimulating effect in animals.Reactions of
            2 with 2-aminophenylcarbonyl derivatives or phenylhydrazine can lead
            to <3,2-b> as well as <3,4-b> annulated pyranes.Regioselective
            reactions in 2- or 4-position of 2 are successful after conversion to the
            enamine 14a, the silylenolether 24 and the lithioenamine
            29.Cycloadditions, cyclocondensations or electrophilic aldolereactions
            yield the pyrano-pyranes 16 and 19a, resp., or the hydroxybenzyl- and
            hydroxybenzylidenpyranes 25 and 30, resp.
 CNR:
            5514997

 Author:
            Sastry, C V Reddy; Rao, K Srinivasa; Krishnan, V S H; Rastogi, K;
            Jain, M L; et al.
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 29, 4, 1990, 396-398
 Title:
            Synthesis and biological activity of some new tetrazolo-benzoxazines
            and bis-tetrazoloqinoxalines
 Abstract:
            A series of new 4H-tetrazolo-<5,1-c><1,4>-benzoxazines (5a-f) and
            bis-tetrazolo<5,1-c:1',5'-a>quinoxalines (8a-8d) have been synthesized
            and evaluated for their CNS, antiinflammatory and antimicrobial
            activities.
 CNR:
            5516318

 Author:
            Agarwal, Alka; Agarwal, Shiv K; Bhakuni, D S
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 29, 9, 1990, 843-847
 Title:
            Antiparasitic agents: Part X - Synthesis of
            2,7-disubstituted-1,6-dihydropyrido<3,4-b>imidazo<4,5-e>indoles as
            anthelmintic agents
 Abstract:
            1,6-Disubstituted-9H-pyrido<3,4-b>indoles (1-4),
            1,5,6-trisubstituted-9H-pyrido<3,4-b>indoles (5-12) and
            2,7-disubstituted-1,6-dihydropyrido<3,4-b>imidazo<4,5-e>indoles
            (13-18) have been synthesized and screened for their anthelmintic and
            antiamoebic activities against Ancylostoma ceylanicum,
            Nippostrongylus brasiliensis, Hymenolepis nana and Entamoeba
            histolytica.Some of these compounds have also been evaluated for
            their CVS, CNS and antiinflammatory activities.However, none of them
            shows any significant activity.
 CNR:
            5516333

 Author:
            Agarwal, Alka; Agarwal, Shiv K; Bhakuni, D S; Gupta, Suman; Katiyar, J C
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 29, 9, 1990, 848-854
 Title:
            Antiparasitic agents: Part XIII- Synthesis and anthelmintic activity of 6- and
            8-(2,4-dioxoquinazolin-3-yl)-1-substituted-9H-pyrido<3,4-b>indoles, 6- and
            8-(2-methyl-5-acetamidobenzimidazol-1-yl)-1-substituted-9H-pyrido<3,4-b>indoles and .....
 Abstract:
            6-(2,4-Dioxoquinazolin-3-yl)-1-substituted-9H-pyrido<3,4-b>indoles (9,10),
            6-(2-metyhyl-5-acetamidobenzimidazol-1-yl)-1-substituted-9H-pyrido<3,4-b>indoles (15,16),
            6-<2-carbomethoxyamino-5-(N,N'-dicarbomethoxyguanidino)benzimidazol-1-yl>-1-phenyl-9H-pyrido<3,4-b>indole
            (17), 8-(2,4-dioxoquinazolin-3-yl)-1-phenyl-9H-pyrido<3,4-b>indole (22) and
            8-(2-methyl-5-acetamidobenzimidazol-1-yl)-1-phenyl-9H-pyrido<3,4-b>indole (25) have been
            synthesized.Evaluation of their anthelmintic activity against Ancylostoma ceylanicum, Nippostrongylus brasiliensis,
            Hymenolepis nana andantiamoebic activity against Entamoeba histolytica shows that compounds 6, 10, 17 and 21
            produce 70-92percent worm reduction against N. brasiliensis and compound 20 exhibits complete clearance of H.
            nana infection at 250 mg/kg dose.The remaining compounds do not exhibit activity of interest.Some of these
            compounds have also been evaluated for their CNS and CVS effects but none shows any promising activity.
 CNR:
            5516334

 Author:
            Tripathi, Ravish C; Singh, H K; Saxena, Anil K
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 29, 9, 1990, 865-869
 Title:
            Synthesis and SAR studies in 1-(g-substituted
            propyl)-4-(4-florobenzoyl/fluorobenzhydryl)piperidines as potential CNS agents
 Abstract:
            The key intermediate 1-(g-chloropropyl)-4-(4-fluorobenzoyl)piperidine (6) has been
            prepared by the condensation of 4-(4-fluorobenzoyl)piperidine (5) with
            1-bromo-3-chloropropane.This on reaction with different amines, thiophenols and
            piperazines gives the title compounds (7-19).Compound 5 on reaction with
            trans-2-phenoxymethylcyclopropane-1-carbonyl chloride yields the
            trans-1-<4-(4-fluorobenzoyl)piperidine-1-ylcarbonyl>2-phenoxymethylcyclopropane
            (20).The potassium borohydride reduction of 9 and 20 affords the corresponding
            alcohols (21 and 22).Some of thesecompounds particularly 10, 15 and 20 show
            potent CNS activity.
 CNR:
            5516337

 Author:
            Pillai, K M R; Kapil, R S; Nand, Nitya
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 29, 9, 1990, 892-894
 Title:
            Synthesis of 2-hydroxymethyl-3-phenyl-piperidine and related
            compounds
 Abstract:
            2-Hydroxymethyl-3-phenylpiperidine (9) and N-substituted
            2-methyl-3-phenylpiperidines (4-6) have been synthesised and tested
            for their CNS activity.None of the compounds shows any significant
            pharmacological activity.
 CNR:
            5516346

 Author:
            Street, Leslie J.; Baker, Raymond; Book, Tracey; Kneen, Clare O.;
            MacLeod, Angus M.; et al.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 33, 10, 1990, 2690-2697
 Title:
            Synthesis and Biological Activity of 1,2,4-Oxadiazole Derivatives:
            Highly Potent and Efficacious Agonists for Cortical Muscarinic
            Receptors
 Abstract:
            The synthesis and biochemical evaluation of novel
            1,2,4-oxadiazole-based muscarinic agonists which can readily
            penetrate into the CNS is reported.Efficacy and binding of these
            compounds are markedly influenced by the structure and
            physicochemical properties of the cationic head group.In a series of
            azabicyclic ligands efficacy and affinity are influenced by the size of the
            surface area presented to the receptor, at the active site, and the
            degree of conformational flexibility.The exo-1-azanorbornane 16a
            represents the optimum arrangement, and this compound is one of the
            most efficacious and potent muscarinic agonists known.In a series of
            isoquinuclidine based muscarinic agonists afficacy and affinity are
            influenced by the geometry between the cationic head group and
            hydrogen bond acceptor pharmacophore and steric bulk in the vicinity
            of the base.The anti configuration represented by 22a is optimal for
            muscarinic activity.Ligands with pKa below 6.5 show poor binding to
            the muscarinic receptor as exemplified by the diazabicyclic derivative
            42.
 CNR:
            5516469

 Author:
            Ilagouma, A. T.; Dornand, J.; Liu, C. F.; Zenone, F.; Mani, J. C.;
            Kamenka, J. M.
 Reference:
            Journal, EJMCA5, Eur.J.Med.Chem.Chim.Ther., EN, 25, 7, 1990,
            609-615
 Title:
            Preparation and study of derivatives and analogues of the
            phencyclidine molecule possessing immunosuppressive properties in
            vitro
 Abstract:
            Derivatives and analogues of the phencyclidine molecule (1-phenyl
            1-(1-piperidino) cyclohexane or PCP) were prepared to investigate
            their immunosuppressive potency and to define the physicochemical
            parameters which may influence this activity recently demonstrated for
            PCP.Most of the tested molecules are more effective than PCP itself.In
            spite of lack of quantitative data, the biological activity appears to be
            dependent upon 3 parameters: conformation, lipophilicity, and the
            empirical Hammett's parameters.The homogeneous conformations
            with a high lipophilicity were the most
            immunosuppressive.Interestingly, such structures appeared to be of
            weak potency on the PCP receptor in the CNS.
 CNR:
            5516616

 Author:
            Kulkarni, Y. D.; Bishnoi, Abha; Dua, P. R.
 Reference:
            Journal, JICSAH, J.Indian Chem.Soc., EN, 67, 1, 1990, 48-51
 Title:
            Synthesis of
            2,8-Disubstituted-6,12-diphenyldibenzo<b,f><1,5>diazocines as
            Possible CNS Drugs
 Abstract:
            Fifteen new
            2,8-disubstituted-6,12-diphenyldibenzo<b,f><1,5>diazocines were
            synthesised and tested for their acute toxicity effects on gross
            behaviour and antireserpine, anticonvulsant and anorexitenic
            activities.
 CNR:
            5519798

 Author:
            Stoffel, Wilhelm
 Reference:
            Journal, ANCEAD, Angew.Chem., GE, 102, 9, 1990, 987-1005
 Title:
            Die Myelinmembran des Zentralnervensystems - essentielle
            makromolekulare Strukturen und Funktion
 Abstract:
            Die Markscheiden der Nervenfasern (Axone) werden von den
            Oligodendrocyten im Zentralnervensystem (CNS) und den
            Schwann-Zellen im peripheren Nervensystem (PNS) aus
            myelinspezifischen komplexen Lipiden und Proteinen in der
            Myelinierungsphase gebildet.Die mehrschichtigen Myelinmembranen
            isolieren die Axone und machen eine schnelle saltatorische
            Erregungsleitung moeglich und bewirken einen verminderten
            Axondurchmesser im Vergleich zu nichtisolierten Axonen.Somit ist die
            Myelinisierung das Ereignis in der Evolution, das entscheidend zur
            Miniaturisierung des Zentralnervensystems (Gehirn und
            Rueckenmark) beitrug.Die Myelinmembran ist morphologisch vor
            allem elektronenmikroskopisch detailliert studiert worden.Biochemisch
            wurde sie in den letzten Jahren sowohl durch die Analyse der
            Lipidkomponenten ( Cholesterin, Phospholipid- und
            Sphingolipidklassen) als auch die der Proteinbausteine auf der
            molekularen Ebene weitgehend aufgeklaert.Eine charakteristische
            Periodizitaet zeichnet das multilamellare System aus.Sie ist bedingt
            durch myelinspezifische Lipide, die eine 5 nm dicke Doppelschicht
            aufbauen.Diese tritt mit dem Basischen Myelinprotein (MBP) der
            cytosolischen Seite der Plasmamembranausstuelpung in
            Wechselwirkung, waehrend das integrale Membranprotein
            Proteolipidprotein (PLP) hydrophile Domaenen sowohl auf der
            cytosolischen als auch der extracytosolischen Oberflaeche der
            Doppelschicht exponiert.Eine Vielzahl von proteinchemischen wie
            immuntopochemischen Befunden wurde in einem
            Myelinmembranmodell zusammengefasst.Molekularbiologische
            Untersuchungen fuehrten zur Aufschluesselung der Genstrukturen der
            Myelinproteine und ihrer Chromosomenlokalisation.Der Prozess der
            Myelogenese, die zeitliche und ortsspezifische Expression der
            Myelinprotein-Gene im Gehirn, kann nun mit molekular- und
            zellbiologischen Techniken analysiert werden.Mit gentechnischen
            Methoden wurden die Mutationen an den Modellen jimpy-Maus und
            myelin-defiziente Ratte bestimmt.Dabei handelt es sich um
            Tiermodelle, die genetisch bedingten Myelindefekten (Dysmyelinosen)
            beim Menschen entsprechen.Damit wird es moeglich sein, auf der
            molekularen Ebene den Zelltod der Oligodendrocyten zu erforschen,
            der als Folge der Expression mutierter Myelinproteine eintritt und mit
            dem Leben nicht vereinbar ist.Oligodendrocyten und die von ihnen
            synthetisierten Myelinstrukturen sind Zielstrukturen cytotoxischer
            Lymphocyten (Tc), die im Verlauf des demyelinisierenden
            Geschehens bei der Multiplen Sklerose in schubhaft auftretenden
            Entzuendungsherden den Abbau der Myelinscheiden
            einleiten.Tc-Lymphocyten erkennen Myelinstrukturen als Epitope und
            zerstoeren sie.Das sich nun abrundende Bild ueber den molekularen
            Aufbau der Myelinmembran wird auch zu einem besseren
            Verstaendnis der Demyelinisierung auf der molekularen Ebene und
            damit zu therapeutischen Ansaetzen fuehren.
 CNR:
            5520124

 Author:
            Eiden, Fritz; Wuensch, Bernhard; Schuenemann, Juergen
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), GE, 323, 8, 1990,
            481-486
 Title:
            Synthesis and CNS-Activity of
            cis-Pyrano<2,3-b>-<1,4>dioxane-Derivatives
 Abstract:
            The alcoholes 2, the amines 5, 7 and 10, the indole- and
            quinoline-derivatives 13 and 14, the enamines 3 and 4 and the
            silylenolethers 17 and 18 were prepared starting with the title
            compound 1.The 1-(7-phenyl-7-pyranodioxinyl)-piperidines 10-cis and
            10-trans show striking CNS-activity.The trans-isomer is about twice as
            active as the cis-isomer.
 CNR:
            5520928

 Author:
            Gilli, Gastone; Pietrogrande, Maria Chiara; Borea, Pier Andrea
 Reference:
            Journal, JPPMAB, J.Pharm.Pharmacol., EN, 42, 1990, 401-404
 Title:
            Normal Phase HPLC as a Model System of Specific
            Benzodiazepine-receptor Binding
 Abstract:
            The hypothesis that benzodiazepines interact with their receptors in the
            CNS via hydrogen bonding mediated by the carbonyl and imine
            groups has been studied by correlating a physicochemical parameter
            affected by hydrogen bonds potentially accepted or donated by
            benzodiazepines with their binding constants to synaptosomal rat brain
            membranes.The reference physicochemical system chosen was
            normal phase high-performance liquid chromatography on
            m-Bondapack NH2 (propylamine groups chemically bonded to porous
            silica) eluted with mixtures of n-hexane and 2-propanol.A strong
            correlation has been found for binding of the implicated groups to the
            column and the receptor.
 CNR:
            5525836

 Author:
            Stumpf, Ch.; Viernstein, H.
 Reference:
            Journal, JPMSAE, J.Pharm.Sci., EN, 79, 12, 1990, 1062-1064
 Title:
            Pharmacological Actions of Central Nervous System Depressants
            Given Intravenously as Suspensions
 Abstract:
            Three central nervous system (CNS) depressants, methohexital
            (sodium), midazolam (maleate), and flunitrazepam, were given
            intravenously to rabbits in equimolar doses as suspensions and
            solutions.The mean diameters of the particles in the suspensions were
            770, 840, and 460 nm, respectively.The CNS actions were verified by
            recording the bioelectrical activity of the precentral cortex.The
            suspensions were tolerated well.There were no differences in onset,
            duration, and maximal intensity of action between suspension and
            solution of each drug.The results of this study should facilitate
            pharmacological studies of drugs acting on the CNS that are insoluble
            in water.
 CNR:
            5526981

 Author:
            Souza, Eleanor Pinto De; Fernandes, P S
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 29, 10, 1990, 961-965
 Title:
            Synthesis of 3-methyl-1-(2H)-isoquinolinone derivatives and their
            biological activities
 Abstract:
            A series of substituted 3-methyl-1(2H)-isoquinolinones (1-19) have
            been prepared from 7-substituted
            4-carboxy-1H-3-methyl-2-benzopyran-1-one and tested for their CNS
            depressant, anti-convulsant, analgesic, anti-inflammatory,
            cardiovascular and diuretic activities.
 CNR:
            5528118

 Author:
            Wuensch, Bernhard
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), GE, 323, 11, 1990,
            933-936
 Title:
            CNS Active Substances: Synthesis of Epoxybenzoxocines
 Abstract:
            The 2-(2-Bromophenyl)-acetaldehyde acetals 8 are treated with n-BuLi
            and the aldehydes 7 and 11 to form the hydroxyacetales 9 and 12,
            respectively. 9 is cyclized under acidic conditions to the
            epoxybenzoxocine 2; analogously 12 yields the epoxydibenzoxocine 14.
 CNR:
            5529757

 Author:
            Manzini, S.; Meini, S.; Giachetti, A.; Beani, L.; Borea, P. A.; et al.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 40, 11, 1990, 1205-1213
 Title:
            Pharmacodynamic Profile of Isbufylline, a New Antibronchospastic
            Xanthine Devoid of Central Excitatory Actions
 Abstract:
            1,3-Dimethyl-7-isobutylxanthine (isbufylline, TE/06; CAS 90162-60-0)
            is a newly synthesized xanthine derivative.This compound exhibits
            remarkable antibronchospastic properties both in vitro and in vivo (after
            oral or intravenous administration) experimental models.Isbufylline is
            significantly more effective than theophylline in antagonizing
            bronchospasms elicited by spasmogens (capsaicin, arachidonic acid,
            PAF and antigen) which mainly act by a local release of biologically
            active substances proposed to be involved in the pathogenesis of
            asthma.Isbufylline, unlike theophylline, possesses little or no CNS
            excitatory properties.This reduced neuroexcitatory action is probably
            related to the poor affinity of isbufylline, as compared to theophylline, to
            A1 purinoceptor.Indeed, isbufylline is ineffective in antagonizing
            2Cl-adenosine-induced EEG synchronization.In normotensive and
            hypertensive rats oral administration of isbufylline resulted in small
            and transient positive chronotropic and hypotensive response,
            markedly lower than those elicited by theophylline or
            enprofylline.Finally isbufylline exhibits phosphodiesterase inhibitory
            properties, although at concentration 50-100 times higher than those
            exerting spasmolytic effects in isolated bronchial tissues.As a whole
            the pharmacodynamic profile of isbufylline is promising and, in the
            clinical setting, this compound might exert enhanced antiasthma
            effects coupled to a low incidence of central and cardiovascular
            adverse effects.
 CNR:
            5530878

 Author:
            Mokrosz, J. L.; Dukat, Malgorzata; Misztal, S.; Chojnacka-Wojcik, Ewa;
            Tatarczynska, Ewa
 Reference:
            Journal, PHARAT, Pharmazie, EN, 45, 10, 1990, 765-767
 Title:
            Structure-activity relationship studies of CNS agents
 Abstract:
            It has been found that 3-alkoxycarbonyl-b-carbolines are almost
            non-toxic and showed a sedative effect.The quantitative relationship
            between the structure of some 1,2,3,4-tetrahydro-b-carbolines and their
            acute toxicity and sedative effect was found using the Free-Wilson
            approach.
 CNR:
            5532801

 Author:
            Mishra, Pradeep; Shakya, Ashok K.; Agrawal, R. K.; Patnaik, G. K.
 Reference:
            Journal, JICSAH, J.Indian Chem.Soc., EN, 67, 6, 1990, 520-521
 Title:
            A Few 2-(Substituted-acetyl)-amino-5-alkyl-1,3,4-thiadiazoles as CNS
            Depressants
 Abstract:
 CNR:
            5533439

 Author:
            Porszasz, J.; Varga, F.; Porszasz, K. G.; Szolscanyi, J.; Bartho, L.; et al.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 40, 12, 1990, 1340-1345
 Title:
            Pharmacology of the new H1-Receptor Antagonist Setastine
            Hydrochloride
 Abstract:
            Setastine HCl
            (N-(1-phenyl-1-<4-chlorophenyl>)-ethoxy-ethylene-perhydroazepine
            hydrochloride, Loderix; CAS 64294-95-7) is a potent antagonist of
            histamine H1-receptor mediated responses.The antihistamine activity
            of the compound is similar to that of clemastine fumarate in the
            following assays: histamine-induced lethality and bronchospasm in
            guinea-pigs, plasma extravasation in rats, and contractile action in
            isolated guinea-pig ileum.Setastine HCl inhibits anaphylactic shock in
            guinea-pigs sensitized by horse serum.No antiserotonin,
            anticholinergic and antiadrenergic effect of the compound can be
            detected.Setastine HCl has a long lasting (up to 16 h) antihistamine
            effect with a good oral effectiveness.It shows no cardiovascular effects
            in cats.Setastine HCl shows a much weaker CNS depressant activity
            than clemestine fumarate measuring inhibition of
            amphetamine-induced hypermotility, rotarod performance, potentiation
            of ethanol-narcosis in mice, and prolongation of hexobarbital sleeping
            time in rats.In displacement studies (3H-mepyramine) setastine HCl
            had significantly weaker affinity for the central nervous system (CNS)
            H1-receptors than clemastine fumarate.It is concluded that setastine
            HCl is a non-sedative highly active H1-antagonist.
 CNR:
            5533709

 Author:
            Linde, Hermann F. G.; Kraemer, Norbert H.
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), GE, 323, 12, 1990,
            945-948
 Title:
            Potentially CNS-Active Tricyclic Compounds with a Bridged Central
            Ring, IV: Synthesis and Configuration of Partially Hydrogenated
            9,10-Epithioanthracene-S-oxides
 Abstract:
            Research on preparation of 9,10-epithioanthracene sufoxides is
            reported.Sodium metaperiodate, hydrogen peroxide/acetic acid, and
            Oxone were used as oxidizing agents.By using Eu(FOD)3, the
            thermodynamically more stable anti-configuration was assigned to the
            endo-compounds.Isomerization of 8-anti into 8-syn is achieved by
            trimethyloxoniumtetrafluoroborate, but is completely reversible at 0
            deg C.The configuration in the exo-series were derived from those of
            the endo-compounds by 1H-NMR-spectroscopy.
 CNR:
            5533895

 Author:
            Garyaev, A. P.; Kononov, O. V.; Dumpis, M. A.; Piotrovskii, L. B.
 Reference:
            Journal, PCJOAU, Pharm.Chem.J.(Engl.Transl.), EN, 24, 5, 1990,
            335-338
 Title:
            CNS STIMULANT EFFECT OF N-ACYLDERVATIVES OF GLUTAMIC
            AND ASPARTIC ACIDS
 Abstract:
 CNR:
            5535931

 Author:
            Ram, V.J.; Srimal, R.C.; Kushwaha, D.S.; Mishra, L
 Reference:
            Journal, JPCEAO, J.Prakt.Chem., EN, 332, 5, 1990, 629-639
 Title:
            Synthesis of <1,2,4>-Triazoloquinazolinones and Related Compounds
            as Antihypertensive Agents
 Abstract:
            A series of 1,2,4-triazolo<4,3-a>quinazolin-5-ones have been prepared
            to access their therapeutic utility as CNS depressant, spasmolytic and
            hypertensive agents.
 CNR:
            5583212

 Author:
            Srivastava, P. C.; Srivastava, S. K.; Singh, P.
 Reference:
            Journal, JICSAH, J.Indian Chem.Soc., EN, 67, 9, 1990, 740-742
 Title:
            Effect of some Organotin Halides, Pseudohalides and their Complexes
            on Oxidative Enzymes and CNS Activities.
 Abstract:
            Several di- and triphenyltin(IV) halides and pseudohalides have been
            screened for their gross CNS activity (in vivo) and for monoamine
            oxidase and pyruvate oxidase inhibitory activities (in vitro) in rat.The
            compounds were found to be CNS depressants.Ph2SnCl2, Ph3SnCl
            and Ph3SnNCS have shown significant inhibition against both the
            tested enzymes.
 CNR:
            5584800

 Author:
            Murti, V. Aruna; Bhandari, Kalpana; Jain, P. C.; Anand, Nitya
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 28, 1-11, 1989, 385-390
 Title:
            Agents acting on CNS: Part XXXV -
            1-(Benzofuran-2/3-yl)-2/3-aminoalkan-1-ones/-1-ols
 Abstract:
            1-(Benzofuran-2-yl or -3-yl) 2- and 3-aminoalkan-1-ones and
            aminoalkan-1-ols have been synthesized by reaction of 2-(and
            3)-bromoacetylbenzofurans with different amines followed by NaBH4
            reduction of the ketones thus obtained. 2-(and 3)-Acetylbenzofurans on
            Mannich reaction with different amines followed by NaBH4 reduction
            give the required benzofuranoaminopropan-1-ols.None of these
            compounds show any significant activity on the cardiovascular or
            central nervous system.
 CNR:
            5575270

 Author:
            Murti, Aruna; Bhandari, Kalpana; Ram, Siya; Prabhakar, Yenamandra
            S.; Saxena, Anil K.; et al.
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 28, 1-11, 1989, 934-942
 Title:
            Synthesis and QSAR of
            1-aryl-4-(b-2-quinolyl/1-isoquinolylethyl)piperazines and some related
            compounds as hypotensive agents
 Abstract:
            1-Aryl-4-(b-2-quinolylethyl)piperazines (7-27,44,45) have been
            prepared by the condensation of 2-alkenylquinolines and
            1-arylpiperazines.The corresponding
            1-aryl-4-(b-hydroxy-b-2-quinolylethyl)piperazines (34-41) have been
            prepared by the condensation of 2-bromoacetylquinoline with
            1-arylpiperazines followed by LAH reduction of the 2-substituted
            acetylquinolines thus obtained.The 4-quinolylethyl (47-51) and
            1-isoquinolylethyl (53-57) analogs have been prepared by the
            condensation of 4-methylquinoline and 1-methylisoquinoline with the
            appropriate piperazines/amines and formaldehyde under Mannich
            conditions.Most of the compounds exhibit prominent hypotensive
            activity and weak to moderate diuretic, antiinflammatory and CNS
            depressant activities.A QSAR study for hypotensive activity, has been
            carried out and the best correlation is described by the parabolic
            relationship between logP and hypotensive activity (with
            logPo=4.23).Amongst the compounds studied, the centrally acting
            hypotensive 1-(3-methylphenyl)-4-(b-2-quinolylethyl)piperazine (17) is
            found to possess the most suitable profile of hypotensive activity.
 CNR:
            5576968

 Author:
            Agarwal, Alka; Agarwal, Shiv K.; Bhakuni, D. S.; Gupta, Suman; Katiyar, J. C.
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 28, 1-11, 1989, 943-949
 Title:
            Antiparasitic agents:Part VIII - Synthesis of 1,6- and
            1,8-disubstituted-9H-pyrido<3,4-b>indoles and
            2-substituted-1(3),10-dihydro-9-phenylpyrido-<3,4-b>imidazo<4,5-g>indoles
            and their anthelmintic activity
 Abstract:
            1,6-Disubstituted-9H-pyrido<3,4-b>indoles (6-17),
            1-phenyl-8-substituted-9H-pyrido<3,4-b>indoles (18-23), and
            2-substituted-1(3),10-dihydro-9-phenylpyrido<3,4-b>imidazo<4,5-g>indoles
            (28, 29) have been synthesized and evaluated for their anthelmintic activity
            against Ancylostoma ceylanicum, Nippostrongylus brasiliensis and
            Hymenolepsis nana.Compounds 11 and 22 show 100 per cent activity
            against A. ceylanicum and H. nana infection respectively at 250 mg/kg
            dose.The remaining compounds either exhibit low activity or are
            inactive.Some of these compounds have also been evaluated for CNS and
            CVS activities.However, none of these show promising activities.
 CNR:
            5576969

 Author:
            Agarwal, Rajesh; Agarwal, Chapla; Singh, Charanjeet; Misra, V. S.
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 28, 1-11, 1989, 893-896
 Title:
            Synthesis of
            1-substituted-2-oxo-3-chloro/3-(2-chlorophenoxy)-4-(2-arylindol-3-yl)-azetidines
            as CNS active and antiinflammatory agents
 Abstract:
            1-Substituted-2-oxo-3-(2-chlorophenoxy)-4-(2-arylindol-3-yl)azetidines (Va-h)
            have been synthesised by direct reaction of 2-aryl-3-(substituted
            aminomethylenyl)indoles (IIIa-h) with o-chlorophenoxyacetyl chloride in dry
            benzene and Et3N or by reaction of
            1-substituted-2-oxo-3-chloro-4(2-arylindol-3-yl)azetidines (IVa-h) with
            o-chlorophenol in the same medium.Compounds IVa-h have been synthesised
            by the reaction of IIIa-h with chloroacetyl chloride in dry benzene and Et3N.The
            intermediate compounds IIIa-h have been prepared by condensation of
            2-arylindol-3-aldehydes with 4-morpholinoaniline or
            4-amino-N,N-diphenylbenzamide.Compounds IV and V have been found to be
            nontoxic and CNS active.Most of these compounds show significant protection
            against carrageenin-induced paw oedema in mice.
 CNR:
            5577131

 Author:
            Saksena, R. K.; Khan, M. Amin
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 28, 1-11, 1989, 443-444
 Title:
            Synthesis of 2-alkyl/aryl-3-arylhydrazino-quinazolin-4(3H)-ones as
            antibacterial and CNS active agents
 Abstract:
            2-Alkyl/aryl-3-aminoquinazolin-4(3H)-ones (IIa-c) on condensation with
            1-nitroso-2-naphthol and 4-nitrosodiphenylamine, separately furnish
            the corresponding 2-alkyl/aryl-3-aryldiazo-quinazolin-4(3H)-ones (IIIa-c
            and IVa-c) which on subsequent reduction by stannous chloride and
            hydrochloric acid afford
            2-alkyl/aryl-3-arylhydrazino-quinazolin-4(3H)-ones (Va-c and
            VIa-c).The compounds III-VI have been screened for their CNS and
            antibacterial activities.
 CNR:
            5577228

 Author:
            Singh, Rajeshwar; Tripathi, R. C.; Kumar, Ashok; Anand, Nitya
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 28, 1-11, 1989, 486-489
 Title:
            Synthesis and pharmacological evaluation of Mannich bases and
            other related compounds, derived from 2,3-dihydro-1H-inden-1-ones
            and 2,3,4,5-tetrahydrobenzocyclohepten-1H-one
 Abstract:
            Mannich bases and some heterocyclic systems e.g. pyrazolo,
            isoxazolo and 2-aminothiazolo, annealed at 1,2-position of
            5,6-dimethoxy-2,3-dihydro-1H-inden-1-one (3),
            4,5-dimethoxy-2,3-dihydro-1H-inden-1-one (4) and
            6,7-dimethoxy-2,3,4,5-tetrahydro-1H-benzocyclohepten-1-one (5) have
            been synthesised and screened for CNS, CVS, antiinflammatory,
            diuretic and antiarrhythmic activity.None of the compounds shows any
            significant activity except 19, 21 and 23 which cause moderate
            lowering of blood pressure.
 CNR:
            5577778

 Author:
            Zara-Kaczian, Erzsebet; Deak, Gyula; Gyoergy, Lajos
 Reference:
            Journal, ACHUDC, Acta Chim.Hung., EN, 126, 4, 1989, 441-454
 Title:
            POTENTIAL CNS ACTIVE 1-ARYL-2-AMINO-1-ETHANOL
            DERIVATIVES
 Abstract:
            New N-(picolyl)-2-(methylamino)-1-aryl-1-ethanols (I) and their O-acyl
            derivatives (II) were synthesized.Their dopaminomimetic and
            antidepressant biological activities were examined and compared with
            the activities of N-(2-aminobenzyl)-2-(methylamino)-1-aryl-1-ethanols
            (III).It was established that in the reaction of
            N-<(6-methyl-2-pyridyl)methyl> methylamine (2) and styryl oxide, the
            two directions of the splitting of the epoxide ring give rise to two
            different products that were isolated and identified in the form of their
            O-acetyl derivatives (13 and 15, respectively).
 CNR:
            5611898

 Author:
            Perina, Z.; Sarsunova, Magda; Zemanova, Eva; Protiva, M.
 Reference:
            Journal, PHARAT, Pharmazie, GE, 44, 2, 1989, 125-128
 Title:
            Parameters of adsorption chromatography. Part 6: Adsorption
            parameters within a group of substances with CNS activity and their
            importance for the relations between chemical structure and biological
            activity
 Abstract:
            For 38 derivatives of 10-piperidinodibenzo<b,f>thiepine the RF-values
            were determined in various solvent systems using thin-layer
            chromatography to calculate the paratmeters of adsorption
            chromatography.The results were classified according to parameters
            used in Hansch analysis.Moreover correlations with biological values
            determined experimentally were looked for.The parameters of
            adsorption chromatography showed activity in all important regression
            equations.
 CNR:
            5687862

 Author:
            Ife, Robert J.; Catchpole, Keith W.; Durant, Graham J.; Ganellin, C. Robin; Harvey, Carol A.; et al.
 Reference:
            Journal, EJMCA5, Eur.J.Med.Chem.Chim.Ther., EN, 24, 1989, 249-258
 Title:
            Non-basic histamine H1-antagonists. I. Synthesis and biological evaluation of some substituted
            2-(2-pyridylaminoalkylamino)pyrimidones and related compounds
 Abstract:
            Using the combined H1/H2-receptor histamine antagonist, icotidine (SK&F 93319, 5b) as a
            starting point, a series of pyridylaminoalkylaminopyrimidones has been evaluated as potential
            selective H1-receptor antagonists with low ability to penetrate the CNS.The most potent
            compound, SK&F 94070, 34,
            2-<3-(5-chloro-3-methyl-2-pyridylamino)propylamino>-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone
            is shown to be a highly selective H1-receptor antagonist of potency comparable with classical
            antihistamines, both in vitro and in vivo.This compound, which has no strongly basic centre and is
            mainly unprotonated at physiological pH, most likely binds to the receptor as a neutral
            (uncharged) molecule.It exemplifies a new structural type of antagonist which represents an
            important departure from the conventional view of antihistamines as strongly basic amines which
            are predominantly protonated under physiological conditions and believed to interact with the
            receptor in the cationic form.H1-antagonists / antihistamines / histamine / isocytosines /
            aminopyrimidones / halopyridines / CNS penetration
 CNR:
            5725085

 Author:
            Consonni, Roberto; Marco, Antonio De; Zannoni, Giulio; Zetta, Lucia;
            Dijkstra, Klaas
 Reference:
            Journal, GCITA9, Gazz.Chim.Ital., EN, 119, 9, 1989, 475-480
 Title:
            PHOTO-CIDNP NMR STUDIES OF DRUGS OF THE CENTRAL
            NERVOUS SYSTEM DERIVED FROM INDOLE AND PHENOL
            RINGS
 Abstract:
            Photo-Chemically Induced Dynamic Nuclear Polarization combined
            with 1H Nuclear Magnetic Resonance have been used to investigate
            the structure of a number of drugs sharing a common moiety.From the
            photo-CIDNP NMR spectra of Central Nervous System (CNS) drugs
            such as morphine, adrenaline, serotonin and lysergic acid, a common
            pattern emerges for the polarizability of protons in the aromatic region
            of the drugs, or in its neighbourhood.The photo-CIDNP technique,
            used so far mainly for the investigation of aromatic residues in
            proteins, is offered as a novel approach for structural studies of small
            molecules of biological or pharmacological interest.The high
            sensitivity of the technique makes it also quite promising for studies of
            substances of very low solubility, or available only in very small
            amounts, as it is often the case for metabolites.
 CNR:
            5797163

 Author:
            Eiden, Fritz; Eckle, Anton
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), GE, 322, 1989,
            617-627
 Title:
            CNS-Active 4-Phenyl-pyrans: Synthesis and Reactions of
            4-Phenyl-2-piperidino-dihydropyran Carboxylic Esters
 Abstract:
            The enamines 1 react with the enones 2 to give the endo/trans-adducts
            3 diastereoselectively and in high yields.Hydrolysis of the diphenyl
            derivatives 3d,f, and h yields the dicarbonyl compounds 7a-c, which
            are transformed to the 4-phenyl-pyrans 8a-c or (via the mixture of
            hydrolysis products 5/6) to the 4-phenyl-pyran carboxylic esters 9a and
            b.The pyran carbaldehydes 12a-c, obtained from 8a-c, are converted
            into the alcohols 10 and 13, as well as into nitriles 16a and b (via the
            oximes 15a and b).The 2-methyl derivatives 3k and l upon treatment
            with acid give thecyclohexenones 18a and b: with methylmagnesium
            iodide the pyran ring is cleaved and heptanone carboxylic acid esters
            20a-c are formed, from which, by hydrolysis, reduction or reaction with
            hydroxylamine the compounds 21, 22, 23 as well as 24a and b are
            obtained.
 CNR:
            5805978

 Author:
            Linde, Herman F. G.; Cramer, Gisela
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), GE, 322, 1989,
            565-568
 Title:
            Potentially CNS-Active Tricyclic Compounds Containing a Bridged
            Central Ring, II: 9,10-Epoxy-9,10-dihydroanthracenes with
            Dialkylamino Side Chain
 Abstract:
            As a continuation of our efforts on the syntheis of
            9,10-epoxy-9,10-dihydroanthracene compounds with basic side chain
            several substituted 9-aminomethyl derivatives have been prepared by
            Diels-Alder cyclization of substituted benzo<c>furanes with
            benzyne.The benzo<c>furanes were obtained by vacuum flash
            thermolysis of
            1,4-epoxy-1,2,3,4-tetrahydronaphthalene-1-carbonamides which were
            produced by Diels-Alder reaction of 2-furan-carbonamides with
            benzyne and by subsequent hydrogenation.
 CNR:
            5806125

 Author:
            Dlugosz, Anna
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), EN, 322, 1989,
            599-602
 Title:
            Synthesis and Biological Properties of Novel
            Triazolopyrimidopyrimidine-5,8-diones
 Abstract:
            The synthesis of novel
            1,2,4-triazolo<2,3,4-c,d>pyrimido<4,5-d>pyrimidine derivatives has
            been described from N-substituted amides of
            1,2,3,4-tetrahydro-6-methyl-2-oxo-4-thio-5-pyrimidinecarboxylic acid
            1.Amides 1 treated with 80percent hydrazine hydrate, followed by
            aqueous-ethanolic formaldehyde form substituted
            triazolo<4,3-c>pyrimidines which cyclize in pyridine to
            triazolopyrimidopyrimidine derivatives 4.Attention has been paid to the
            synthesis of the 4-arylidenehydrazinopyrimidines 3.Some compounds
            have been tested for antibacterial and anticancer activities and for
            action on CNS.
 CNR:
            5806143

 Author:
            Chumpradit, Sumalee; Kung, Hank F.; Billings, Jeffrey; Kung, Mei-Ping; Pan, Sangren
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 32, 7, 1989, 1431-1435
 Title:
            (+/-)-7-Chloro-8-hydroxy-1-(4'-<(125)I>iodophenyl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine:
            A Potent CNS D-1 Dopamine Receptor Imaging Agent
 Abstract:
            Synthesis, radiolabeling, and in vitro and in vivo properties of an iodinated benzazepine,
            (+/-)-7-chloro-8-hydroxy-1-(4'-<(125)I>iodophenyl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine,
            <(125)I>FISCH, as a potential imaging agent for evaluation of central nervous system (CNS) D-1
            dopamine receptors in humans, were investigated.After an iv injection, this benzazepine
            derivative showed good brain uptake in rats (2.27, 1.40, 0.55percent dose/whole brain at 2, 15,
            and 60 min, respectively).The striatum/cerebellum ratio was high (2.47 at 60 min after the
            injection).The binding affinity of this agent in rat striatum tissue preparation displayed a Kd of 1.43
            +/- 0.15 nM.Competition data (in vitro) showed the following rank order of potency: SCH-23390 >
            (+/-)-FISCH > (+/-)-IBZP >> apomorphine > WB 4010 > ketanserin ca. spiperone.The preliminary
            data suggest that the agent is highly selective for the CNS D-1 receptor.
 CNR:
            5808015

 Author:
            Botros, S.; Lipkowski, A. W.; Larson, D. L.; Stark, P. A.; Takemori, A. E.;
            Portoghese, P. S.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 32, 9, 1989, 2068-2071
 Title:
            Opioid Agonist and Antagonist Activities of Peripherally Selective
            Derivatives of Naltrexamine and Oxymorphamine
 Abstract:
            A series of b-naltrexamine and b-oxymorphamine derivatives that
            contain ionizable moieties coupled to 6b-amino group were
            synthesized in an effort to develop antagonists and agonists that have
            negligible access into the central nervous system (CNS).Among the
            b-naltrexamine derivatives 1-7, all displayed partial agonism on the
            guinea pig ileal longitudinal muscle preparation except for aspartyl
            derivative 6, which was a full agonist with activity in the range of
            morphine.The b-oxymorphamine derivatives 8-12 were all full agonists
            with potencies ranging from 1.5 to 6.1 times that of morphine.Among
            the compounds evaluated in mice for antiniciceptive or opioid
            antagonist activities, aspartyl derivative 6 possessed the greatest
            difference between peripheral (po or iv) and icv equiactive antagonist
            doses.Compared to naltrexone, 6 was > 100 times more potent by the
            icv route, but 6000-10000 times less potent when administered po or
            icv.The present study suggests that zwitterionic groups are highly
            effective in preventing penetration of ligands into the CNS.Such
            ligands may be useful pharmacologic tools for investigation of
            peripheral opioid mechanisms.Moreover, they could find clinical
            applications when the central actions are unwanted.
 CNR:
            5808028

 Author:
            Pop, Emil; Wu, Whei-Mei; Bodor, Nicholas
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 32, 8, 1989, 1789-1795
 Title:
            Chemical Delivery Systems for Some Penicillinase-Resistant
            Semisynthetic Penicillins
 Abstract:
            Chemical delivery systems (CDS's) based on a dihydropyridine <->
            quaternary pyridinium ion redox system analogous to the naturally
            occurring NADH <-> NAD+ system were synthesized for a group of
            staphylococcal penicillinase resistant penicillins, including methicillin,
            oxacillin, cloxacillin, and dicloxacillin, in order to improve their
            penetration of the central nervous system (CNS).The CDS's are
            penicillin monoesters of gem-diols in which the other hydroxyl group is
            esterified by the dihydrotrigonelline carrier.The CDS's were found to be
            much more lipophilic than the parent drugs by comparing their log k'
            values used as lipophilicit y indexes.A study of the chemical oxidation
            of the CDS's performed by a UV spectrophotometric method showed
            relatively slow reaction.Stability studies were performed in buffers and
            different animal tissues for both the CDS's and the quaternary salt type
            derivatives.These studies showed that the CDS's were oxidized to the
            quaternary salt forms at neutral and basic pH and added water at lower
            pH.The quaternary salts released the parent drugs both in buffer and in
            vitro.A preliminary in vivo distribution study in the rat and rabbit
            demonstrated blood-brain barrier (BBB) penetration by the CDS,
            whereas no drug was detected by administering the drug itself.
 CNR:
            5808089

 Author:
            Chakrabarti, Jiban K.; Hotten, Terrence M.; Pullar, Ian A.; Steggles,
            David J.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 32, 10, 1989, 2375-2381
 Title:
            Synthesis and Pharmacological Evaluation of CNS Activities of
            <1,2,3>Triazolo<4,5-b><1,5>-, Imidazolo<4,5-b><1,5>-, and
            Pyrido<2,3-b><1,5>benzodiazepines.
            10-Piperazinyl-4H-1,2,3-triazolo<4,5-b><1,5>benzodiazepines with
            Neuroleptic Activity
 Abstract:
            The synthesis of <1,2,3>triazolo<4,5-b><1,5>-,
            imidazolo<4,5-b><1,5>-, and pyrido<2,3-b><1,5>benzodiazepines is
            described.The antidopaminergic and anticholinergic activities of the
            compounds have been examined by the respective in vitro
            <3H>spiperone and <3>QNB receptor binding assay.The neuroleptic
            potential has been further evaluted in terms of their ability to produce
            hypothermia and catalepsy in mice and a conditioned avoidance
            response in rats.Only compounds from the triazolobenzodiazepine
            series show antipsychotic potential.The lack of activity in the
            imidazolo- and pyridobenzodiazepine series indicates that the basicity
            of the heteroarene moiety may be determinant for activity.
 CNR:
            5842173

 Author:
            Quraishi, M. A.
 Reference:
            Journal, FRMCE8, Farmaco, EN, 44, 7-8, 1989, 753-758
 Title:
            SYNTHESIS AND CNS ACTIVITY OF SOME NEW SUBSTITUTED
            INDENO <1,2-c> PYRAZOLES
 Abstract:
            Some new
            1-(6'-substituted-4'-methylquinol-2'-yl)-3-methylindeno<1,2-c>pyrazoles
            (Va-d) have been synthesized by the condensation of
            2-acetylindane-1,3-dione (I) with 2-hydrazino-4-methyl-6-substituted
            quinolines (IIa-d), followed by cyclodehydration with polyphosphoric
            acid and Wolff-Kishner reduction.Compounds (IVa-d) showed
            noticeable CNS activity.
 CNR:
            5863663

 Author:
            Sprio, V.; Caronna, S.; Migliara, O.; Pertuso, S.; Matera, M.
 Reference:
            Journal, FRMCE8, Farmaco, IT, 44, 9, 1989, 809-818
 Title:
            SINTESI DI DERIVATI PIRAZOLO<3,4-e><1,4> DIAZEPIN-4,7-DIONI ATTIVI SUL
            SISTEMA NERVOSO CENTRALE
 Abstract:
            The synthesis of
            1-phenyl-5,8-dimethyl-1,4,5,6,7,8-hexahydro-pyrazolo<3,4-e><1,4>diazepin-4,7-dione
            and of
            1-phenyl-3,5,8-trimethyl-1,4,5,6,7,8-hexahydro-pyrazolo<3,4-e><1,4>diazepin-4,7-dione
            is described.These compounds exhibit activity on CNS in animals.
 CNR:
            5863668

 Author:
            Schmidt, D.; Ried, S.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., GE, 39, 1a, 1989, 156-158
 Title:
            Clinical Relevance of Calcium Antagonists in the Treatment of
            Epilepsy
 Abstract:
            The antiepileptic effects of dihydropyridine derivates and flunarizine
            are currently evaluated in controlled clinicial trials following earlier
            reports of their antiepileptic action in experimental animal models of
            epilepsy and promising pilot studies in human epilepsy.Other calcium
            antagonists such as verapamil or diltiazem have proved less effective
            in experimental models.They penetrate poorly into the CNS
            (Verapamil) and are difficult to evaluate clinically due to relevant
            pharmacokinetic interactions with antiepileptic drugs.Key words:
            Antiepileptic drugs * Calcium antagonists * Calcium channels *
            Epilepsy * Ion channels
 CNR:
            5864488

 Author:
            Murata, T.; Sakaya, S.; Hoshino, T.; Umetsu, T.; Hirano, T.; Nishio, S.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 39, 8, 1989, 860-866
 Title:
            General Pharmacology of Beraprost Sodium 1st Communication: Effect on the central nervous system
 Abstract:
            Beraprost sodium (sodium
            (+/-)-(1R*,2R*,3aS*,8bS*)-2,3,3a,8b-tetrahydro-2-hydroxy-1-<(E)-(3S*)-3-hydroxy-4-methyl-1-octen-6-ynyl>-1H-cyclopenta<b>benzofuran-5-butyrate,
            TRK-100) is an orally active epoprostenol(prostaglandin I2, PGI2) analogue.Its effect on the central nervous system (CNS) was studied. 1.When
            orally administered in mice, beraprost sodium at 0.3 mg/kg caused a flush of skin, a suppression of spontaneous motility, and a fall of body
            temperature.At 1 mg/kg and more, it showed obvious sedation, prolongation of hexobarbital hypnosis, and analgesic action in acetic acid-induced
            writhing test.However, even at 3 mg/kg beraprost sodium neither induced ataxia nor had anticonvulsant activity.Hypothermia was also observed in
            rabbits at 1 mg/kg (p.o. and i.v.). 2.When intravenously administered, beraprost sodium exerted long-lasting action on the CNS, while its
            pharmacological effects resembled those of PGI2. 3.Oral administration of beraprost sodium did not inhibit aggregation toxicity induced by
            methamphetamine(20 mg/kg i.p.) in mice.Beraprost sodium at doses higher than 1 mg/kg enhanced aggregation toxicity induced by
            methamphetamine (5 mg/kg i.p.), while intracerebral ventricular administration of beraprost sodium failed to enhance it. 4.In rat spinal reflex,
            intravenous administration of beraprost sodium (0.1 mg/kg) slightly enhanced monosynaptic reflex and at a high dose (1 mg/kg) suppressed
            polysynaptic reflex. 5.In the rabbit EEG, intravenous administration of beraprost sodium at a high dose (1 mg/kg) showed some effects such as the
            continuous pattern of wakefulness and a fall in power of the EEG.These findings demonstrate that beraprost sodium has actions similar to those of
            PGI2 such as sedation and hypothermia, in addition to alterations in spinal reflex and the EEG at the high dose.Probably, these actions may be
            attributed to rather a secondary effect mediated through the cardiovascular respiratory system than direct action on the CNS. - Key words:
            Antithrombotics.Beraprost sodium, central nervous system effects, general pharmacology.Epoprostenol, analogue.TRK-100
 CNR:
            5875189

 Author:
            Valenzuela, Raul; Li, Choh Hao; Huidobro-Toro, J. Pablo
 Reference:
            Journal, JPPMAB, J.Pharm.Pharmacol., EN, 41, 1989, 92-96
 Title:
            Lack of Mixed Agonist-Antagonist Properties of
            <Gln8-Gly31>-bh-EP-Gly-Gly-NH2 and <Arg9,19,24,28,29>-bh-EP in the
            Rat Vas Deferens Neuroeffector Junction: Studies with Naloxone,
            b-Funaltrexamine and ICI 174,864
 Abstract:
            The 1-27 truncated fragment of bh-endorphin (bh-EP) as well as
            <Gln8,Gly31>-bh-EP-Gly-Gly-NH2 or <Arg9,19,24,28,29>-bh-EP exhibited
            opiate agonist activity in the rat vas deferens bioassay; the potency of
            these peptides was 3 to 6 times less than that of bh-EP.None of these
            compounds exhibited any degree of antagonism towards the inhibitory
            action of bh-EP.Naloxone antagonized and reversed the inhibitory
            action of bh-EP and its analogues though with varying potencies.The
            apparent naloxone-pA2 value for bh-EP was 8.94; that for
            <Gly8-Gly31>-bh-EP-Gly-Gly-NH2 was 8.08 and that for
            <Arg9,19,24,28,29>-bh-EP was 8.38. b-Funaltrexamine (b-FNA) potently
            antagonized the inhibitory action of bh-EP following non-equilibrium
            kinetics.Tissue preincubation with 10 nM b-FNA for 60 min followed by
            extensive washing caused a 10-fold inrease in the bh-EP
            IC50.However, 10 nM bFNA caused only a 1.2 increase in the IC50 of
            <Gln8,Gly31>-bh-EP-Gly-Gly-NH2 and a 4.1-fold increase in the IC50
            of <Arg9,19,24,28,29>-bh-EP.In contrast, preincubation of the tissue with
            3 mM ICI 174,864 did not modify the potency of bh-EP or its structural
            analogues.However, a 60 min pretreatment with 10 mM b-FNA
            followed by the addition of 3 mM ICI 174,864 revealed a futher
            decrease in the potency of the opiopeptins compared with tissues
            exposed to b-FNA alone or ICI 174,864 alone.In conclusion, the
            inhibitory action of these peptides is remarkably sensitive to b-FNA
            antagonism; in addition the peptides act as pure opiate agonists in
            marked contrast with the agonist-antagonist properties described in the
            CNS.
 CNR:
            5878446

 Author:
            Bjoerkman, Sven; Elisson, Lars Ove; Gabrielsson, Johan
 Reference:
            Journal, JPPMAB, J.Pharm.Pharmacol., EN, 41, 1989, 160-163
 Title:
            Pharmacokinetics of Quinacrine after Intrapleural Instillation in Rabbits
            and Man
 Abstract:
            Quinacrine was given by intrapleural instillation or intravenous infusion
            to 10 rabbits.The uptake of quinacrine from the pleural space was
            rapid and complete.The mean absorption half-life was approximately 7
            min and the mean bioavailability was slightly in excess of
            100percent.Similar absorption characteristics generally applied in
            man, in a pilot study in four patients.In three of them, peak quinacrine
            plasma concentrations were reached that were far above the normal
            therapeutic range.Known systemic side-effects of of quinacrine
            comprise CNS stimulation, toxic psychosis and convulsions.In view of
            the high bioavailability and the large doses used for pleural sclerosing
            (pleurodesis) in patients, neurological disease and psychiatric
            disturbances that prediscope to CNS toxicity should be considered as
            contraindications to intrapleural quinacrine.
 CNR:
            5879255

 Author:
            Johnson, G.; Boxer, P. A.; Drummond, J. T.; Boyd, D. K.; Anderson, R.
            J.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 39, 4, 1989, 432-437
 Title:
            Identification and Evaluation of O-Alkyl Substituted Hydroxamic Acids
            as Potent in vitro Inhibitors of the Hepatic Glycine Cleavage System
            and Investigation of Their Action on in vivo Central Nervous System
            Glycine Concentration
 Abstract:
            The identification and evaluation of an extensive series of O-alkyl
            substituted hydroxamic acids as potent in vitro inhibitors of the hepatic
            glycine cleavage system is described.An investigation of the action of
            selected examples on the in vitro brain glycine cleavage system and
            their influence on in vivo plasma and central nervous system glycine
            concentrations following systemic administration is also reported. -
            Key words: O-Alkylhydroxamates; Glycine, cleavage system, CNS
            concentration; Hydroxamic acids, O-alkyl substituted, synthesis
 CNR:
            5883178

 Author:
            Fargeas, M. J.; Fioramonti, J.; Bueno, L.
 Reference:
            Journal, JPPMAB, J.Pharm.Pharmacol., EN, 41, 1989, 534-540
 Title:
            Involvment of Different Receptors in the Central and Peripheral Effects
            of Histamine on Intestinal Motility in the Rat
 Abstract:
            The effects of histamine on intestinal motility have been investigated in
            conscious rats, fed or fasted, using an electromyographic
            method.Histamine peripherally administered (10 mg kg-1) in 15 h
            fasted rats induced an inhibition followed by a period of irregular
            spiking activity disrupting the doudenojejunal migrating myoelectric
            complexes (MMC) and suppressed the postgrandial motor spiking
            activity when administered 50 min after a meal.The selective agonist
            of the H1-receptors, 2-pyridylethylamine (2-PEA) induced an irregular
            spiking activity while dimaprit acting on H2-receptors, inhibited the
            MMC pattern.Effects of peripherally administered histamine were
            antagonized by previous administration of chlorpheniramine (0.5 mg
            kg-1 i.p.) and in a lesser extent by cimetidine (10 mg kg-1
            i.p.).Histamine (1-10 mg) administered intracerebroventricularly (i.c.v.)
            in fasted rats increased the motorcycle frequency and immediately
            restored the MMC pattern when given to fed rats.Among the three
            agonists of the H1-H2-and H3-receptors (2-PEA, dimaprit and
            R-a-methylhistamine, respectively) only R-a-methylhistamine (1-10 mg
            i.c.v.) was able to reproduce this effect.It is concluded that the effects of
            histamine on intestinal motility were centrally and peripherally
            mediated involving mainly H1-receptors at the peripheral level and
            H3-receptors at the CNS level.
 CNR:
            5918494

 Author:
            Prochazka, Zdenko; Ancans, Juris E.; Slaninova, Jirina; Machova,
            Alena; Barth, Tomislav; et al.
 Reference:
            Journal, CCCCAK, Collect.Czech.Chem.Commun., EN, 53, 11A, 1988,
            2604-2616
 Title:
            SYNTHESIS AND PROPERTIES OF ANALOGUES OF
            VASOPRESSIN WITH 1-AMINOCYCLOPROPANE-1-CARBOXYLIC
            ACID IN POSITION 9
 Abstract:
            Solid phase methodology on benzhydrylamine resin was used for the
            synthesis of three analogues of vasopressin with non-coded amino
            acid, 1-aminocyclopropane-1-carboxylic acid, in position 9.Two
            analogues of lysine-vasopressin (<Lys8,Acc9>vasopressin (I) and
            Gly3-<Lys8,Acc9>vasopressin (II) and one analogue of
            arginine-vasopressin (<Arg8,Acc9>vasopressin (III)) have been
            synthesized.The dubious value of the biological activity of
            <Lys8,D-Ala9>vasopressin was reevaluated and
            <Lys8,L-Ala9>vasopressin was also synthesized and tested for the
            comparison.Differences in solution conformation of these two
            analogues were studied by 1H and 13C NMR spectroscopy.Biological
            activities of all analogues were either significantly lowered or almost
            completely eliminated.Analogues I-III were found to be completely
            inactive in analgesia and the CNS activities tested (active and passive
            avoidance).
 CNR:
            5565653

 Author:
            Garg, C. P.; Sharma, Vinay Prabha; Chhabra, Vinod; Kapoor, R. P.
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 27, 1988, 469-471
 Title:
            Synthesis of 3-<2-(Pyrazol-1-yl)-4-thiazolyl>-2-methylchromones
 Abstract:
            A number of 3-<2-(pyrazol-1-yl)-4-thiazolyl>-2-methylchromones (Va-o)
            have been synthesized by the condensation of
            3-bromoacetyl-2-methylchromones (IVa-d) with
            1H-pyrazol-1-thiocarboxamides (IIIa-c).Some of these compounds
            have been screened for CNS/CVS, antiinflammatory and diuretic
            activities.
 CNR:
            5574238

 Author:
            Saksena, R. K.; Khan, Amin
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, <B> 27, 1-12, 1988,
            295-297
 Title:
            Synthesis of Some New
            Bis(4-oxo-3-phenyl-6,8-disubstituted-quinazolin-2-yl) Disulphides,
            Sulphides, Sulphones and Alkylenedisulphides and Their CNS
            Activities
 Abstract:
            2-Mercapto-3-phenyl-6,8-disubstituted-quinazolin-4(3H)-ones (I) have
            been dimerised to bis(4-oxo-3-phenyl-6,8-disubstituted-quinazolin-2-yl)
            disulphides (II).Reaction of I with a,w-dihaloalkanes yields
            a,w-bis(4-oxo-3-phenyl-6,8-disubstituted-quinazolin-2-yl) alkylene
            disulphides (III).Compound I reacts with thionyl chloride to afford the
            sulphides (IV) which on oxidation with hydrogen peroxide furnish the
            respective sulphones (V).Some of these compounds have been
            screened for their CNS activities.
 CNR:
            5574460

 Author:
            Varma, Rajendra S.; Chauhan, Sudha; Prasad, C. R.
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 27, 1-12, 1988, 438-442
 Title:
            Synthesis of Substituted 2-Phenylbenzothiazoles and
            5(6)-Nitro-1,3-disubstituted-benzimidazoline-2-thiones as CNS Active
            Agents.
 Abstract:
            p-(Benzothiazolyl)phenoxyacetylhydrazine (2), obtained by the
            hydrazinolysis of ethyl-p-(2-benzothiazolyl)phenoxyacetate (1), when
            reacted with salicylaldehyde gives
            N-(2-hydroxybenzylidene)-p-(2-benzothiazolyl)phenoxyacetylhydrazine
            (3).Condensation of isatin and N-methylisatin with 2 affords the
            corresponding hydrazones (4 and 5).The hydrazone 4 on Mannich
            reaction gives 6.Mannich reaction of benzoxazolin-2-one,
            benzoxazoline-2-thione and benzothiazoline-2-thione with
            2-(p-aminophenyl)benzothiazole (7) furnishes 8, 9 and 10
            respectively.Condensation of isatin and N-methylisatin with 7 gives 11
            and 12 respectively.The Mannich condensation of 11 with
            morpholine/piperidine yields 13.Treatment of acetanthranil with 7 gives
            14 which on reaction with benzaldehyde affords
            3-<p-(2-benzothiazolyl)phenyl>-2-styryl-4(3H)-quinazolinone (15).
            1,3-Bis(amino/anilinomethyl)-5(6)-nitrobenzimidazoline-2-thiones (16)
            have been obtained by the Mannich condensation of
            5(6)-nitrobenzimidazoline-2-thione with different amines/anilines.
 CNR:
            5576724

 Author:
            Shutske, Gregory M.; Huger, Francis P.
 Reference:
            Journal, JHTCAD, J.Heterocycl.Chem., EN, 25, 2, 1988, 703-709
 Title:
            Synthesis of 3-Aryl-6H-isoxazolo<3,4-d>pyrazolo<3,4-b>pyridines and
            3-Aryl-6H-isoxazolo<5,4-d>pyrazolo<3,4-b>pyridines
 Abstract:
            The synthesis and characterization of a number of
            3-aryl-6H-isoxazolo<3,4-d>pyrazolo<3,4-b>pyridines and
            3-aryl-6H-isoxazolo<5,4-d>pyrazolo<3,4-b>pyridines from common
            precursors, 5-benzoyl-4-chloro-1H-pyrazolo<3,4-b>pyridines, has been
            described.The structures were determined by unabiguous chemical
            synthesis and by isolation and 13C nmr analysis of some key, isolated,
            intermediates.The ability of these compounds to displace
            <3H>flunitrazepam from CNS binding sites was also observed.
 CNR:
            5631533

 Author:
            Bartsch, Herbert; Erker, Thomas
 Reference:
            Journal, JHTCAD, J.Heterocycl.Chem., EN, 25, 1988, 1151-1154
 Title:
            Studies on the Chemistry of O,N- and S,N-Containing Heterocycles. 3
            <1>. Synthesis of 1,5-Benzothiazepines with Potential CNS Activity
 Abstract:
            The synthesis of a series of novel
            triazolo<3,4-d><1,5>benzothiazepines 6 and 7, obtained from the
            activated 1,5-benzothiazepine derivatives 3 and carbohydrazides 4, is
            described.Under mild reaction conditions some intermediates 5 can be
            isolated.
 CNR:
            5636026

 Author:
            Hough, Leslie; Sinchareonkul, Lee V.; Richardson, Anthony C.; Akhtar,
            Farida; Drew, Michael G. B.
 Reference:
            Journal, CRBRAT, Carbohydr.Res., EN, 174, 1988, 145-160
 Title:
            BRIDGED DERIVATIVES OF SUCROSE: THE SYNTHESIS OF
            6,6'-dithiosucrose, 6,6'-epidithiosucrose, and 6,6'-epithiosucrose
 Abstract:
            Selective iodination and bromination of sucrose at C-6 and C-6' has
            been accomplished by reactions with
            iodine-triphenylphosphine-imidazole and carbon
            tetrabromide-triphenylphosphine-pyridine, respectively.Substitution of
            the bromo groups in 6,6'-dibromo-6,6'-dideoxysucrose hexa-acetate by
            CNS(1-), AcS(1-), and Me2NCS2(1-) took place without complications,
            but when EtOCS2K was used, a complex reaction sequence took
            place leading to 6,6'-epithiosucrose hexa-acetate.Similarly, reaction of
            the dibromo derivative with K2CS3 afforded mainly the
            6,6'-episulphide together with 6,6'-epidithiosucrose hexa-acetate,
            which was also formed from the dibromide by sequential treatment
            with thiourea and sodium metabisulphite.Oxidation of the episulphide
            with sodium metaperiodate afforded solely the (R)-sulphoxide, and
            oxidation with hydrogen peroxide afforded the sulphone.The
            episulphide, the episulphide S,S-dioxide, and the episulphide all
            showed conformational instability of the ring containing the sulphur
            atom(s), as indicated by the n.m.r. spectra, but the episulphide S-oxide
            did not show this behaviour.
 CNR:
            5664189

 Author:
            Maeda, Hiroshi; Suzuki, Mamoru; Sugano, Hiroshi; Yamamura, Michio;
            Ishida, Ryuichi
 Reference:
            Journal, CPBTAL, Chem.Pharm.Bull., EN, 36, 1, 1988, 190-201
 Title:
            Synthesis and Central Nervous System Actions of
            Thyrotropin-Releasing Hormone Analogs Containing a
            1-Oxo-1,2,3,4-tetrahydroisoquinoline Moiety
 Abstract:
            In order to find compounds having selective central nervous system
            (CNS) actions, various thyrotropin-releasing hormone (TRH) analogs
            in which the pyroglutamic acid residue is replaced by
            (3S)-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Otc-OH)
            and related derivatives were prepared and their CNS actions were
            investigated in mice.Otc-His-Pro-NH2 (9a) showed 3.5-10 times
            stronger CNS actions than TRH (1).However, it was also 3-4 times
            more potent than TRH in thyrotropin (TSH)-releasing activity.Keywords
            - TRH analog; central nervous system;
            1-oxo-1,2,3,4-tetrahydroisoquinoline; spontaneous locomotor activity;
            reserpine-induced hypothermia effect; pentobarbital anesthesia effect
 CNR:
            5681528

 Author:
            Cingolani, Gian Mario; Claudi, Francesco; Venturi, Fabrizio
 Reference:
            Journal, EJMCA5, Eur.J.Med.Chem.Chim.Ther., EN, 23, 1988,
            291-294
 Title:
            Indolizine derivatives with biological activity V.
            1-(2-Aminoethyl)-2-methylindolizine and its N-alkyl derivatives
 Abstract:
            In continuing the search for new biologically active agents in the
            indolizine field, 1-(2-aminoethyl)-2-methylindolizine and some N-alkyl
            derivatives have been synthesized.Preliminary pharmacological
            evaluation showed that these compounds exhibited anti-acetylcholine,
            anti-histamine and central nervous system (CNS) depressant
            activities.Keywords - substituted indolizines / anti-acetylcholine activity
            / anti-histamine activity / CNS activity
 CNR:
            5724443

 Author:
            Roske, I.; Umatov, E.A.; Pevcova, E.I.; Rathsack, R.; Oehme, P.
 Reference:
            Journal, PHARAT, Pharmazie, EN, 43, 5, 1988, 339-343
 Title:
            Influence of adrenal demedullation on stress induced alterations within
            the general adaptation behaviour of August-rats
 Abstract:
            Based on new theoretical aspects of functional participation of adrenal
            glands in adaptation process, resulting from supplement of Selye's
            stress concept by intergration of peptidergic system, stress related
            adaptation behaviour of sham operated and demedullated August-rats,
            characterized by a high stress-sensitivity, were investigated.To
            characterize the stress related behaviour the following parameters
            were investigated: - Number of rats surviving the exposure, -
            alterations of body mass, - occurence of ulcers and hyperaemia in
            stomach, - blood pressure behaviour, - organ mass of adrenals,
            pituitaries and hypothalami in total, - SPLIR in adrenals, pituitaries,
            hypothalami in total as well as in their special nuclei areas of N.
            ventromedialis and N. lateralis.The following conclusions can be
            drawn from experimental results: - The important role of adrenal
            medulla in regulation of adaptive processes is given by the interaction
            between of its catecholamine system and its regulatory system of
            peptides (substance P,Opioids).Whereas demedullation itself makes
            visible alterations which are connected with the loss of
            adrenal-catecholamine system, additional stressor exposition makes
            visible alterations connected with the loss of adrenal-regulatory
            system. - Investigations show differences in the sensitivity of reaction
            against the influence of stressors between catecholamine system
            (more sensitive) and regulatory system of adrenal medulla of
            August-rats. - Demedullation has a different influence on alterations
            induced by mild manipulation stress (activation of catecholamine
            system) and by immobilization (activation of regulatory system).The
            influence of manipulation stress is inhibited and the influence of
            immobilization is increased by demedullation.- Results of this
            investigations refer to the existence of feedback relations between the
            adrenal medulla and pituitary as well as between adrenal medulla and
            hypothalamus. - Furthermore there are indications, that the adrenal
            medulla takes part in the regulation of extraadrenal sympathetic
            activity. - The experimental data give furthermore a hint for the
            existence of a high stress sensitivity of August-rats primary caused by
            the CNS. - The different sensitivity in relation to the induction of
            stressresponse between the catecholamine system and the regulatory
            system of adrenal medulla could be an additional reason for the
            formation of pathophysiological stress reactions of August-rats. -
            Differences in the formation of stress-induced alterations between
            Wistar-rats and August-rats respectively are discussed concerning their
            cause. - The high sympathetic nervous activity of August-rats includes
            the participation of a high portion of adrenal catecholamines.
 CNR:
            5733496

 Author:
            Kosary, Judit; Kovacs-Szabo, Ilona; Kiraly, Ildiko; Kasztreiner, Endre
 Reference:
            Journal, PHARAT, Pharmazie, EN, 43, 8, 1988, 527-528
 Title:
            The CNS effects of 5-aminobenzoic acids inhibiting the biosynthesis of
            prostaglandins
 Abstract:
            It was found that the 2,5-diaminobenzoic acid derivatives 1 activating
            the biosynthesis of prostaglandins have CNS side effects.The
            replacement of the 2-NH group in 1 by O or S resulted an inhibition of
            prostaglandin biosynthesis and increased CNS activity.
 CNR:
            5733548

 Author:
            Sangwan, Naresh K.; Verma, Braham S.; Dhindsa, Kuldip Singh
 Reference:
            Journal, JPCEAO, J.Prakt.Chem., EN, 330, 1, 1988, 137-141
 Title:
            Synthesis and Biological Properties of Substituted
            2H-1-Benzopyran-2-ones and
            2H,10H-Benzo<1,2-b:3,4-b'>dipyran-2,10-diones
 Abstract:
            In continuation of our earlier studies in substituted pyrazoles,
            benzopyrano<4,3-c>pyrazoles, benz<6,7>indazoles,
            benz<6,7>cyclohepta<1,2-c>pyrazoles, pyrazolo<4,3-c>quinolines and
            2/4H-1-benzopyran-2/4-ones, which exhibit various biological
            activities, namely antimicrobial, antifertility and CNS/CVS activities
            some 2H-1-benzopyran-2-ones incorporating a pyrazolyl moiety have
            been prepared and tested in view of antimicrobial activity.
 CNR:
            5733803

 Author:
            Eiden, Fritz; Gmeiner, Peter
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), GE, 321, 1988,
            397-401
 Title:
            Synthesis of CNS-active Pyrane, thiopyrane and piperidine annulated
            Oxa-Carbabenzomorphanes
 Abstract:
            Tetrahydro-3-pyranone (13a) and -thiopyranone (13b) react with
            salicylidene acetone (1a) and NaH in DMSO to give the pyrane and
            thiopyrane annulated oxaanaloges of carbabenzomorphanes: 13a
            reacts regioselectively in 4-position to the B/C-trans- and
            cis-derivatives 10a and 12, 13b reacts in 2- and 4-position, so the
            regioisomeres 14a and 16a, resp. 17a and 19 are formed.The reaction
            of the enamine 20 with the salicylidene acetone derivative 1b yields
            the piperidine annulated oxacarbabenzomorphane 22, via the
            octahydroisoquinoline derivative 21 as an intermediate.
 CNR:
            5776384

 Author:
            Bourguignon, Jean-Jacques; Schoenfelder, Angele; Schmitt, Martine;
            Wermuth, Camille-Georges; Hechler, Viviane; et al.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 31, 5, 1988, 893-897
 Title:
            Analogues of g-Hydroxybutyric Acid. Synthesis and Binding Studies
 Abstract:
            Substituted 4-hydroxybutyric (GHB) or trans-4-hydroxycrotonic acids
            (T-HCA) and structurally related compounds were synthesized and
            submitted to <3H>GHB binding.Structure-activity relationship studies
            highlighted for <3H>GHB binding (a) the necessity of a nonlactonic,
            relatively extended conformation of the g-hydroxybutyric chain, (b) the
            existence of some bulk tolerance in the vicinity of the hydroxyl group,
            and (c) the high sensitivity toward isosteric replacements of the
            carboxyl or the hydroxyl groups.T-HCA has been recently identified as
            a naturally occuring substance in the central nervous system (CNS)
            and shows a better affinity than GHB.Our findings are in favor of the
            presence in the CNS of specific GHB binding sites, which are different
            from the GABA and the picrotoxin binding sites, and for which T-HCA
            may be endoqenous ligand.
 CNR:
            5800035

 Author:
            Kreutzberger, Alfred; Schlaefer, Irmtraut
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), GE, 321, 1988,
            827-830
 Title:
            CNS Depressants, VII: (Diallylamino)-1,3,5-triazines Substituted at the
            Triazine Nucleus
 Abstract:
            The reaction of 2,4-dichloro-6-(diallylamino)-1,3,5-triazine (1) with
            long-chain primary (2a-b) or cyclic secondary (2c-f) amines leads to
            chloro(diallylamino)-1,3,5-triazines (3a-f) substituted at the triazine
            nucleus.Transformation of the diallylamino group into the aziridine ring
            is a mass spectrometric fragmentation pathway characteristic for
            structures of type 3.Compound 3a exhibits striking CNS depressant
            activity.Furthermore, structures of type 3 exhibit antiprotozoic,
            anthelminthic and insect growth regulatory activities.
 CNR:
            5806567

 Author:
            Eiden, Fritz; Gmeiner, Peter
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), GE, 321, 1988,
            321-324
 Title:
            Oxabenzomorphanes: Synthesis of CNS-effective
            Hexahydro-2,7-methano-1,5-benzoxazonines
 Abstract:
            The reaction of the dihydro-2,6-methano-benzoxocin 4a with HN3
            produces the tetrahydro-2,7-methano-1,4- respectively
            -1,5-benzoxazonines 3a and 5.The methyl derivatives 4b and c,
            however, give only one regioisomer (3b and c, resp.).Reduction with
            LiAlH4 leads to the amines 6a,b and c or 8a, methylation to 6d and e
            resp. 8b.
 CNR:
            5807244

 Author:
            Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; Freidinger, R.
            M.; et al.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 31, 12, 1988, 2235-2246
 Title:
            Methods for Drug Discovery: Development of Potent, Selective, Orally
            Effecive Cholecystokinin Antagonists
 Abstract:
            3-(Acylamino)-5-phenyl-2H-1,4-benzodiazepines, antagonists of the
            peptide hormone cholecystokinin (CCK), are described.Developed by
            reasoned modification of the known anxiolytic benzodiazepines, these
            compounds provide highly potent, orally effective ligands selective for
            peripheral (CCK-A) receptors, with binding affinities approaching or
            equaling that of the natural ligand CCK-8.The distinction between
            CCK-A receptors on the one hand and CNS (CCK-B), gastrin, and
            central benzodiazepine receptors on the other is demonstrated by
            using the structure-activity profiles of the new compounds.Details of
            the binding of these agents to CCK-A receptors are examined, and the
            method of development of these compounds is discussed in terms of
            its relevance to the general problem of drug discovery.
 CNR:
            5837734

 Author:
            Maurelli, M.; Marchioni, E.; Tartara, A.
 Reference:
            Journal, FRPSAX, Farmaco Ed.Sci., EN, 43, 2, 1988, 161-168
 Title:
            CENTRAL EXTRAENDOCRINE EFFECTS OF VASOPRESSIN AND
            OXYTOCIN IN THE RABBIT
 Abstract:
            The effect of vasopressin and oxytocin on cerebral electrical activity,
            somatic behavior, heart rate and rectal temperature of
            non-anesthetized rabbits was studied.Both peptides induced EEG and
            behavioral activation and proved to be active in modifying heart rate
            and rectal temperature.EEG and behavioral changes, as well as
            autonomic effects seemed to be independent of one another, thus
            suggesting different points of attack of the peptides at CNS level.
 CNR:
            5864824

 Author:
            Marchioni, E.; Maurelli, M.; Tartara, A.
 Reference:
            Journal, FRPSAX, Farmaco Ed.Sci., EN, 43, 3, 1988, 267-276
 Title:
            ELECTROENCEPHALOGRAPHIC AND AUTONOMIC EFFECTS OF
            CENTRALLY ADMINISTERED NEUTROTENSIN IN THE RABBIT
 Abstract:
            Neutrotensin perfusion into the third ventricle of the unanesthetized
            rabbit induces an increase of the total power density spectrum of the
            cortex, without modifying the electrical activity of the cornu Ammonis
            dorsale.This evidence suggests a direct action of the peptide on the
            cortical neurons and seems to exclude the involvement of the
            brainstem reticular formation in inducing the electroencephalographic
            pattern.Simultaneously Neurotensin produces an evident behavioural
            excitation and a moderate thermolytic effect.The
            electroneurophysiologic, automatic and behavioural changes are
            independent from one another and seem to depend on an action
            exerted by Neutrotensin at various levels in the CNS.
 CNR:
            5864833

 Author:
            Ahmad, Ishtiaq
 Reference:
            Journal, JICSAH, J.Indian Chem.Soc., EN, 65, 1988, 362-364
 Title:
            Some Newer Quinazolones as Psychotropic Agents
 Abstract:
            Some substituted-quinazolones have been synthesised with a view to
            evaluate CNS activity.The psyhopharmacological sreening has shown
            to possess anticonvulsant activity, observed against
            penlylenetetrazole.In vivo MAO inhibitory effect of these compounds
            were studied during oxidative deaminisation of benzylamine using rat
            brain homogenate.
 CNR:
            5865032

 Author:
            Joshi, Krishna C.; Jain, Renuka; Sharma, Kanti; Bhattacharya, S. K.;
            Goel, R. K.
 Reference:
            Journal, JICSAH, J.Indian Chem.Soc., EN, 65, 1988, 202-204
 Title:
            Studies in Spiro-heterocycles. Part-XII. Synthesis of some Fluorine
            containing
            Spiro<3H-indole-3,4'(4H)-pyrano<2,3-d>pyrimidine>-2,5',7'(1H)-triones
            as CNS Agents
 Abstract:
            Several new fluorine containing
            spiro<3H-indole-3,4'(4H)-pyrano<2,3-d>-pyrimidine>-2,5',7'(1H)-triones
            were synthesised by the Michael reaction of
            3-(carboethoxycyano/dicyano)methylene-indol-2-ones with barbituric
            acid; the former being obtained from indole-2,3-dione and
            malononitrile/ethyl cyanoacetate.The compounds were characterised
            by ir, pmr, 19F nmr, 13C nmr and mass spectral studies.Representative
            compounds were tested on mice for CNS activities (analgesic and
            anticonvulsant) and the effects were also observed against
            amphetamine induced stereotypy on conditioned avoidance response
            and on potentation of pentobarbitone sodium hypnosis.
 CNR:
            5865176

 Author:
            Brewster, Marcus E.; Estes, Kerry S.; Bodor, Nicolas
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 31, 1988, 244-249
 Title:
            Improved Delivery through Biological Membranes. 32. Synthesis and
            Biologiccal Activity of Brain-Targeted Delivery Systems for Various
            Estradiol Derivatives
 Abstract:
            Brain-targeted delivery systems based on the dihydropyridine <*>
            pyridinium salt redox interconversion were synthesized for estradiol,
            estradiol 3-benzoate, and ethynylestradiol.Initial biological evaluation
            indicated that while all four compounds synthesized excreted central
            estrogenic activity as measured by serum LH suppression, only the
            delivery system based on the 17-substituted estradiol and
            ethynylestradiol demonstrated prolonged action (>12 days).The
            17-(1-methyl-1,4-dihydronicotinic acid ester) of ethynylestradiol
            behaved in a similar manner to the previously described estradiol
            analogue in various assays.Tissue distribution studies in rats showed
            that administration of the ethynylestradiol derivative resulted in high
            sustained levels of the corresponding pyrimidinium salt in the central
            nervous system (CNS) while blood levels of the oxidized metabolite
            rapidly fell.The sustained brain levels were associated with a
            prolonged release of ethynylestradiol.By 24 h, posttreatment, no
            ethynylestradiol was found by HPLC in the blood while levels of over
            20 ng/g of tissue were detected in the CNS.This enhanced central
            delivery gave a dose- and time-dependent LH suppression, which
            indicated a three- to fivefold ibcreased potency compared with the
            corresponding estradiol derivative.
 CNR:
            5868901

 Author:
            Molinengo, L.; Fundaro, A. M.; Cassone, M. C.
 Reference:
            Journal, JPPMAB, J.Pharm.Pharmacol., EN, 40, 1988, 821-822
 Title:
            Action of a chronic arecoline administration on mouse motility and on
            acetylcholine concentrations in the CNS
 Abstract:
            The modifications of mouse motility and of the levels of acetylcholine
            (ACh) in two sections of the CNS caused by a chronic administration of
            4.5; 9.5; 28.5 and 60 mg kg-1 of arecoline for 20 days have been
            studied.At low doses (4.5 and 9.5 mg kg-1 day-1), arecoline caused no
            modification of the ACh levels and of the motility.The higher doses
            (28.5 and 60 mg kg-1 day-1) caused a reduction of the mouse motility
            and an increase of the ACh levels in the subcortical structures of the
            CNS of the mouse.
 CNR:
            5877474

 Author:
            Claussen, C.-F.; Claussen, E.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., GE, 38, 3, 1988, 396-399
 Title:
            Antivertiginous Effect of Vitamin B6 on Experimental, Minocycline
            Induced Vertigo in Man
 Abstract:
            By means of a former investigation it has been proved
            equilibriometrically that the application of 7 x 100 mg minocycline may
            induce a central equilibrium dysregulation of the brainstem type.It was
            the purpose of this study to further assure that the minocycline induced
            brainstem vertigo is due to a destabilization of a supervisory
            g-aminobutyric acid (GABA)ergic loop from the archeocerebellum upon
            the pontomedullary vestibular regulating pathways.As it is
            pharmacologically known that pyridoxine is essential for the synthesis
            of GABA, an inhibitory CNS neurotransmitter, 2 separate double blind
            trials on 20 healthy young persons each were carried out after the
            intake of 7 x 100 mg minocycline during 3 days with and without 7 x 40
            mg pyridoxine simultaneously.These trials were checked against an
            additional placebo or initial non drug investigation.In all the 40 test
            persons it could be proved that the amount of vertigo and nausea
            symptoms was increased significantly due to the application of
            minocycline only.However, when combining minocycline with vitamin
            B 6, the vertigo and nausea symptoms as well as the nystagmus signs
            from the monaural and the binaural vestibular ocular tests as well as
            the vestibular spinal signs from the craniocorpography recordings of
            the stepping and the standing procedures were remarkably
            reduced.There were no statistical differences between the initial or
            placebo trials with versus the trials a combination of minocycline with
            vitamin B 6.The same holds for the vestibular vegetative reactions,
            measured by the simultaneous electrocardiography during the
            vestibular tests.All the equilibriometric tests applied showed a
            significant destabilization under the influence of a pure monocycline
            loading.Thus, vitamin B 6 proves that GABA-ergic control mechanisms
            are involved in the minocycline induced vertigo states of the brainstem
            type.Therefore, vitamin B 6 may also be regarded as an antivertiginous
            drug for central dysequilibrium states.Key words: Brainstem,
            ponto-medullary .Central vestibular dysregulation, equilibriometric
            measurements .Minocycline, clinical studies, neurootological studies
            .Vertigo, minocycline induced .Vitamin B 6.
 CNR:
            5885264

 Author:
            Lakhan, R.; Singh, R. L.
 Reference:
            Journal, FRPSAX, Farmaco Ed.Sci., EN, 43, 19, 1988, 745-752
 Title:
            POTENTIAL CNS ACTIVE AGENTS II - Studies of
            4(3H)-quinazolinones
 Abstract:
            Some new 2-carbamoylmethylthio- and
            2-(w-dimethylaminoalkyl)thio-3-aryl-7-chloro-4(3H)-quinazolinones
            have been prepared from 2-thio-3-aryl-7-chloro-4(3H)quinazolinones
            as the key intermediate.Five of the synthetic compounds were
            screened for their CNS activities on mice and found to be either CNS
            depressants or stimulants.
 CNR:
            5917035

 Author:
            Kung, Hank F.; Kasliwal, Ravindra; Pan, Sangren; Kung, Mei-Ping; Mach, Robert
            H.; Guo, Yu-Zhi
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 31, 5, 1988, 1039-1043
 Title:
            Dopamine D-2 Receptor Imaging Radiopharmaceuticals: Synthesis,
            Radiolabeling, and in Vitro Binding of (R)-(+)- and
            (S)-(-)-3-Iodo-2-hydroxy-6-methoxy-N-<(1-ethyl-2-pyrrolidinyl)methyl>benzamide
 Abstract:
            In developing central nervous system (CNS) dopamine D-2 receptor imaging
            agents, enantiomers (R)-(+)- and (S)-(-) isomers, of
            3-<125I>iodo-2-hydroxy-6-methoxy-N-<(1-ethyl-2-pyrrolidinyl)methyl>benzamide,
            <125I>IBZM, were synthesized, and their in vitro binding characteristics were
            evaluated in rat striatum tissue preparation.The (S)-(-)-<125I>IBZM showed high
            specific dopamine D-2 receptor binding (Kd = 0.43 nM, Bmax = 0.48 pmol/mg of
            protein).Competition data of various ligands for IBZM binding displayed the
            following rank order of potency: spiperone > (S)-(-)-IBZM > (+)-butaclamol >>
            (R)-(+)-IBZM > (S)-(-)-BZM > dopamine > ketanserin > SCH23390 >>
            propanolol.The results indicate that <125I>IBZM bind specifically to the dopamine
            D-2 receptor with stereospecificity.The <125I>IBZM is potentially useful as an
            imaging agent for the investigation of dopamine D-2 receptors in humans.
 CNR:
            5940884

 Author:
            Walser, A.; Flynn, T.
 Reference:
            Journal, JHTCAD, J.Heterocycl.Chem., EN, 24, 1987, 683-688
 Title:
            Quinazolines and 1,4-Benzodiazepines. XCVI. Compounds Derived
            from Benzodiazepine-2-acetic Acid
 Abstract:
            1,4-Benzodiazepine-2-acetic acid derivatives were prepared and
            converted to compounds with a heterocyclic ring fused to the a-face of
            the benzodiazepine system.Representatives of
            pyrido<1,2-a><1,4>benzodiazepines,
            pyrimido<1,6-a><1,4>benzodiazepines and
            <1,3>oxazino<3,4-a><1,4>benzodiazepines are described.Some of the
            compounds showed marked CNS-activity as measured by the
            antimetrazole test which is a well established primary screening
            method for assessment of benzodiazepine type activity.
 CNR:
            5632127

 Author:
            Rao, Jyoti; Saxena, Anil K.; Saxena, R. M.; Singh, H. K.; Kar, K.;
            Srimal, R. C.
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 26, 1-12, 1987, 761-765
 Title:
            Synthesis of N-<3-Aryl(thio/sulphono)propyl>heterocyclics as Potential
            CNS/CVS Agents
 Abstract:
            A number of N-<3-aryl(thio/sulphono)propyl>heterocyclics (6-13,
            19-21) have been synthesized by the condensation of
            g-chloropropylaryl sulphides and sulphones (3-5 and 18) with
            appropriate nitrogen heterocyclics.The 4-aminophenyl derivatives in
            case of sulphides (14-17) and sulphones (22-24) have been prepared
            by hydrolysis of the corresponding 4-acetamidophenyl derivatives (6-9,
            19-21).The 4-amino- or 4-fluorosulphone (27/30) has been obtained by
            the condensation of the corresponding g-chloropropyl
            4-amino/fluorophenyl sulphone (26/29) with
            octahydropyrazinopyridoindole, the former (26) being obtained by the
            hydroysis of 18 while 29 from 26 by decomposition of its diazonium
            salt (28).These compounds in general exhibit good hypotensive
            activity in addition to other activities like antiinflammatory, PCA,
            diuretic and anxiolytic.
 CNR:
            5643635

 Author:
            Toja, Emilio; Francesco, Giuseppe Di; Barone, Domenico; Baldoli,
            Emiliana; Corsico. Nerina; Tarzia, Giorgio
 Reference:
            Journal, EJMCA5, Eur.J.Med.Chem.Chim.Ther., EN, 22, 1987,
            221-228
 Title:
            Anti-hypertensives:
            1-alkyl-2-arylpiperazinoethyl-1H-naphth<1,2-d>imidazoles
 Abstract:
            L 15848 (8b citrate) is a new anti-hypertensive agent belonging to the
            class of 1-alkyl-2-aminoethylnaphth<1,2-d>imidazoles.It lowers blood
            pressure in spontaneously hypertensive rats (50 mg/kg, p.o.) and in
            conscious normotensive and renal hypertensive dogs (5-20 mg/kg,
            p.o.).The decrease in systolic blood pressure is dose related and long
            lasting, and is evident for periods of up to 7 h.A slight and transient
            decrease in heart rate was observed in the renal hypertensive
            dogs.CNS depressant effects were not apparent after L 15848
            administration in doses up to 100 mg/kg, p.o. (rat, mouse and dog).The
            criteria for the selection of L 15848 are discussed and two alternative
            synthetic pathways are presented.Keywords -
            naphth<1,2-d>imidazoles / N1-alkyl-1,2-naphthalendiamines /
            anti-hypertensives / L15848
 CNR:
            5669823

 Author:
            Regnier, Gilbert L.; Guillonneau, Claude G.; Duhault, Jacques L.;
            Tisserand, Francoise P.; Saint-Romas, Guy; Holstorp, Sophie M.
 Reference:
            Journal, EJMCA5, Eur.J.Med.Chem.Chim.Ther., EN, 22, 1987,
            243-250
 Title:
            New xanthine derivatives with potent and long lasting
            anti-bronchoconstrictive activity
 Abstract:
            Twenty eight new derivatives of 8-aminoalkyl substituted xanthine
            have been synthesized.They all have demonstrated a potent
            anti-bronchoconstrictive effect in the guinea pig and some of them
            have a very long duration of action (>48 h).Among them, one
            compound: 1-methyl 3-isobutyl 8-(4-benzhydryl piperazino
            ethyl)xanthine (57) (S 9795) has been selected for clinical trials in
            asthmatic patients because of its long duration of action, its lack of
            CNS stimulating effects and its inhibiting action on mast cell
            degranulation and phosphodiesterase activity.Keywords -
            8-aminoalkyl substituted xanthines / benzhydryl piperazine / piperidine
            / ethylenediamine / anti-bronchoconstrictors / phosphodiesterase
            inhibitors / asthma
 CNR:
            5671252

 Author:
            Prostakov, N. S.; Soldatenkov, A. T.; Fedorov, V. O.; Bagdadi, V. M.;
            Borisov, M. M.
 Reference:
            Journal, PCJOAU, Pharm.Chem.J.(Engl.Transl.), EN, 21, 6, 1987,
            408-411
 Title:
            SYNTHESIS AND CNS ACTION OF 1-AZAFLUORENE
            DERIVATIVES
 Abstract:
 CNR:
            5702216

 Author:
            Baklanova, O. V.; Padeiskaya, E. N.
 Reference:
            Journal, PCJOAU, Pharm.Chem.J.(Engl.Transl.), EN, 21, 8, 1987,
            577-581
 Title:
            CHEMOTHERAPEUTIC ACTIVITY OF KETOCONAZOLE,
            AMPHOGLUCAMINE, AND MYCOHEPTINE IN A WHITE MICE
            MODEL OF CNS CANDIDIASIS
 Abstract:
 CNR:
            5703079

 Author:
            Agarwal, Shiv K.; Saxena, Anil K.; Jain, Padam C.; Sur, R. N.; Srimal, Rikhab C.;
            et al.
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 26, 1-12, 1987, 642-646
 Title:
            Synthesis and Structure-Activity Relationship in
            1-Aryloxy-3-<N1-(N4-arylpiperazinyl)>propanes
 Abstract:
            1-<6-(1,2,3,4-Tetrahydroquinoloxy)>-3-<N1-(N4-arylpiperazinyl)>propanes (6, 7)
            have been synthesized by the condensation of
            1-acetyl-1,2,3,4-tetrahydroquinoline with
            1-chloro-3-<N1-(N4-arylpiperazinyl)>propane, followed by acid hydrolysis of the
            resulting
            1-<6-(1-acetyl-1,2,3,4-tetrahydroquinoloxy)>-3-<N1-(N4-arylpiperazinyl)>propane
            (4, 5). 1-<4-(N1-Substituted
            pyrimidinyl)phenoxy>-3-<N1-(N4-phenylpiperazinyl)>propanes (20, 21) have
            been prepared by the condensation of
            1-chloro-3-<N1-(N4-phenylpiperazinyl)>propane with
            1-<4-(1-(2-methylmercapto-4-substituted-6-oxopyrimidinyl)>phenol (18, 19).
            1-(Hydroxymethylphenoxy) -3-<N1-(N4-arylpiperazinyl)>propanes (22-27) have
            been obtained by the NaBH4 reduction of
            1-(formylphenoxy)-3-<N1-(N4-arylpiperazinyl)>propanes.The LiAlH4 reduction
            and hydrolysis of 1-(3-cyanophenoxy)-3-<N1-(N4-phenylpiperazinyl)>propane
            afforded the corresponding
            1-(3-aminomethylphenoxy)-3-<N1-(N4-phenylpiperazinyl)>propane (28) and
            1-(3-carboxyphenoxy)-3-<N1-(N4-phenylpiperazinyl)>propane (29).Some of
            these compounds show potent CNS depressant, hypotensive and
            a-adrenoceptor blocking activities.
 CNR:
            5703817

 Author:
            Tateoka, Yuji; Kimura, Toshiyuki; Watanabe, Kazuhito; Yamamoto,
            Ikuo; Ho, Ing Kang
 Reference:
            Journal, CPBTAL, Chem.Pharm.Bull., EN, 35, 12, 1987, 4928-4934
 Title:
            Potentiating Effects of N1,N3-Diallyluracil, N1,N3-Diallylthymine and
            N1,N3-Diallyl-6-methyluracil on Pentobarbital-Induced Sleep and
            Diazepam-Induced Motor Incoordination
 Abstract:
            N-allyl derivatives of uracil (U), thymine (T) and 6-methyluracil (6-MU)
            were prepared, and their pharmacological activities (hypnotic activity
            and anticonvulsant activity against pentylenetetrazol (PTZ)-induced
            seizures) and interactions with three sedative-hypnotics <pentobarbital
            (PB), barbital (B) and diazepam (DZ)> were investigated in
            mice.N1,N3-Diallyluracil (DAU) alone exhibited hypnotic and
            anticonvulsant activities.None of the other allyl derivatives showed
            both pharmacological activities.As regards interactions, most of the
            compounds tested prolonged PB-induced sleep at either 80 or
            160mg/kg, i.p.Further, U, T, and 6-MU (160mg/kg, i.p.) also prolonged
            the PB-induced sleeping time.DAU showed a prolonging effect on
            PB-induced sleep when given by intracerebroventricular (i.c.v.)
            injection.DAU, N1,N3-diallylthymine (DAT) and N1-monoallyluracil
            (N1-MAU) significantly prolonged the B-induced sleeping time at a
            dose of 160mg/kg, i.p. Further, DAU, and DAT (40mg/kg, i.p.)
            enhanced DZ-induced motor incoordination.These results indicate that
            U and related compounds possess central nervous system
            (CNS)-depressant effects and DAU is the most potent among the
            N-allyl derivatives tested. Keywords --- N1,N3-diallyluracil;
            N1,N3-diallylthymine; N1,N3-diallyl-6-methyluracil; hypnotic activity;
            anticonvulsant activity; barbiturate-induced sleep; diazepam-induced
            motor incoordination
 CNR:
            5724615

 Author:
            Amanuma, Fusao; Kameyama, Tsutomu
 Reference:
            Journal, CPBTAL, Chem.Pharm.Bull., EN, 35, 7, 1987, 2973-2978
 Title:
            Pharmacological Studies of Furo<3,2-b>indole Derivatives. III.
            Correlation between Analgesic Effect and Effect on Central Nervous
            System of N-(3-Piperidinopropyl)-4-methyl-6-trifluoromethyl
            Furo<3,2-b>indole-2-carboxamide (FI-302) in Mice
 Abstract:
            N-(3-Piperidinopropyl)-4-methyl-6-trifluoromethyl
            furo<3,2-b>indole-2-carboxamide (FI-302) is a new non-steroidal
            anti-inflammatory compound.The analgesic effect of FI-302 and its
            effect on the central nervous system (CNS) were compared with those
            of aspirin, chlorpromazine and chlordiazepoxide in mice subjected to
            various experimental conditions.FI-302 showed an analgesic effect
            with all the methods used, but aspirin, chlorpromazine and
            chlordiazepoxide showed analgesic effects only with the acetic
            acid-induced writhing method.Moreover, FI-302 inhibited spontaneous
            motor activity and fighting behavior induced by isolation and
            foot-shock, but had no effect on the hexobarbital-induced sleeping
            time.Aspirin had no effect on the CNS, but chlorpromazine and
            chlordiazepoxide showed inhibitory effects with all the methods
            used.Fighting behavior is related to emotional response, and pain is
            associated with emotional responses such as distress and
            anxiety.Thus, it is suggested that FI-302 is a new analgesic compound
            which has an inhibitory effect on the emotional response in the CNS.
 CNR:
            5726516

 Author:
            Knabe, Joachim; Buech, Horst P.; Lampen, Peter
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), GE, 320, 9, 1987,
            807-813
 Title:
            Derivatives of Barbituric Acid, XXXIX: Pharmacological Activity of the
            Enantiomers of Barbiturates with a Basic Side Chain at the Nitrogen
            Atom
 Abstract:
            The enantiomers of the N-(aminoethyl)barbiturates 7a, 7b, 8b and 8d
            influence the motoric behavior when given i.v. to rats.They elicit
            central-nervously caused ataxia and hyperkinetic movements, which,
            on higher doses, change to CNS excitatoric symptoms (tonic-clonic
            convulsions).The dose dependence of the effect shows the
            R(-)enantiomer to be more active than the S(+)enantiomer.After i.p.
            application the enantiomers of 7a-7c and 8a-8d prolong the sleeping
            time of an anesthesia caused by hexobarbital.Again the
            R(-)enantiomer is more active than the S(+)enantiomer.Also, the effect
            is dose dependent, but the enantiomers of 8d prolong the sleeping
            time more than linearly.With a constant dose of 8d prolongation of the
            sleeping time is time dependent: With both enantiomers prolongation
            is maximal 15 min after application: 3 hours later the effect disappears
            completely.
 CNR:
            5776319

 Author:
            Bindra, Jasjit S.; Rastogi, Shri Nivas; Patnaik, G. K.; Anand, N.; Rao, K.
            G. Gurudath; et al.
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 26, 1987, 318-329
 Title:
            Synthesis, Pharmacological Activities and Physico-chemical
            Properties of 4-(Substituted
            amino/N4-arylpiperazinyl/aminocarbonyl)-2,
            3-polymethylenequinolines
 Abstract:
            A series of N-substituted-aminoacridines (27-29) and 4-(substituted
            amino, N4-arylpiperazinyl and
            aminocarbonyl)-2,3-polymethylenequinolines (30-103) have been
            synthesized and tested for their CNS effects.Compounds with
            significant activity have been identified, which include
            4-(n-butylamino)-2,3-tetramethylene quinoline (35, centbucridine) and
            4-(n-heptylamino)-2,3-tetramethylenequinoline (40) as local
            anesthetics, 4-(n-butylamino)-2,3-pentamethylenequinoline (61) as
            antihistaminic and
            4-(N4-phenylpiperazinyl)-2,3-pentamethylenequinoline (76) as
            analeptic.Witha view to determining relationship between the
            physico-chemical properties and biological activities of these
            molecules, pKa, lipophilicity and DNA binding of a few selected
            compounds of each type have been studied.
 CNR:
            5842016

 Author:
            Wanwimolruk, Sompon; Levy, Gerhard
 Reference:
            Journal, JPMSAE, J.Pharm.Sci., EN, 76, 7, 1987, 503-507
 Title:
            Effect of Age on the Pharmacodynamics of Phenobarbital and Ethanol
            in Rats
 Abstract:
            The purpose of this investigation was todetermine the effect of age on
            the sensitivity of the central nervous system (CNS) to the depressant
            action of phenobarbital and ethanol.For this purpose, one or the other
            of these drugs was administered by slow iv infusion to male rats of
            various until the animals lost righting reflex.The drug concentrations at
            that time in serum, brain, and cerebrospinal fluid were determined.The
            results obtained in studies on 1, 9, and 18-month-old Sprague-Dawley
            rats and on 7, 16, and 24-month-old Fischer-344 rats showed that
            phenobarbital concentrations at the pharmacologic endpoint
            decreased with increasing age, indicative of an increased sensitivity of
            older animals to the CNS depressant effect of the barbiturate.Similar
            studies with ethanol on Sprague-Dawley rats (only) showed
            substantially higher drug concentrations at all sampling sites in
            5-week-old animals than in 9- and 12-month-old animals at the onset
            of loss of righting reflex, but no significant differences between the 9-
            and 12-month-old groups.This investigation, which was designed to
            exclude or account for pharmacokinetic variables and to avoid
            confounding secondary effects, such as hypothermia and development
            of acute functional tolerance, showed a substantial increase in CNS
            sensitivity to phenobarbital and ethanol with increasing age in rats
            between the age of 1 and 9 months, and a less pronounced increase
            (phenobarbital) or no significant change (ethanol) in rats between 9
            and 18 months of age.
 CNR:
            5868917

 Author:
            Hansch, Corwin; Bjoerkroth, J. P.; Leo, A.
 Reference:
            Journal, JPMSAE, J.Pharm.Sci., EN, 76, 9, 1987, 663-687
 Title:
            Hydrophobicity and Central Nervous System Agents: On the Principle
            of Minimal Hydrophobicity in Drug Design
 Abstract:
            The problem of getting drugs across the so-called blood-brain barrier
            (BBB) has long been under extensive investigation; however, the other
            side of the problem, that of keeping drugs out of the central nervous
            system (CNS), has not been studied so intently.As we strive to make
            more and more refined drugs with fewer side effects, the problem of
            keeping drugs out of the CNS has possibly become more important
            than getting them in.The role of lipophilicity has long been recognized
            as being important in CNS penetration by chemicals, but we believe
            that not enough attention has been devoted to just exactly what is
            meant when it is said that ''a lipophilic drug is needed for CNS
            penetration.'' How lipophilic? Can hydrophilic properties keep drugs
            out of the CNS? How hydrophilic should they be? There are other
            reasons for making drugs hydrophilic.Hydophobic drugs, other factors
            being equal, are more inhibitory of biochemical systems than
            hydrophilic congeners.Evidence is beginning to show that cytochrome
            P450 is induced in direct proportion to hydrophobicity by a variety of
            compounds, and cytochrome P450 may produce modifications in
            lipophilic molecules in the body.Hydrophobic drugs are more slowly
            eliminated.This report discusses these problems in terms of the
            octanol-water (log P) hydrophobic scale.The principle is proposed that,
            without convincing evidence to the contrary, drugs should be made as
            hydrophilic as possible without loss of efficacy.Antihistamines are
            discussed in terms of what kind of hydrophobic-hydrophilic balance is
            best to avoid CNS-related problems.
 CNR:
            5868948

 Author:
            Kalix, P.; Geisshuesler, S.; Brenneisen, R.
 Reference:
            Journal, JPPMAB, J.Pharm.Pharmacol., EN, 39, 1987, 135-137
 Title:
            The effect of phenylpentenyl-khatamines on the release of radioactivity
            from rat striatal tissue prelabelled with <3H>dopamine
 Abstract:
            The CNS-stimulating properties of leaves of the khat shrub (Catha
            edulis, Celastraceae) are presumed to be due mainly to (-)-cathinone,
            a phenylpropylamine alkaloid that has been shown to have an
            amphetamine-like releasing effect at physiological cathecolamine
            storage sites.Recently, several phenylpentenylamine alkaloids have
            been identified in khat leaves, and these have been evaluated, in vitro,
            in the present study for their ability to induce release of radioactivity
            from <3H>dopamine prelabelled rat striatal tissue.It was found that the
            phenylpentenylamines have a weak releasing effect, and are therefore
            considered unlikely to play an important role in the stimulating
            properties of khat leaves.
 CNR:
            5875085

 Author:
            Hughes, Richard A.; Andrews, Peter R.
 Reference:
            Journal, JPPMAB, J.Pharm.Pharmacol., EN, 39, 1987, 339-343
 Title:
            Structural and conformational analogy between cholecystokinin and
            ergopeptines
 Abstract:
            The central nervous system (CNS) peptide cholecystokinin (CCK) and
            the ergopeptine alkaloids exhibit common pharmacology in the brain,
            particularly via catecholaminergic systems.We report here structural
            similarities between CCK and the ergot alkaloids, and the subsequent
            conformational analysis of the peptide undertaken to establish whether
            or not a three-dimensional relationship exists between the
            compounds.Two low-energy conformations of CCK that mimic the
            ergopeptine ergotamine are identified, one arising from an X-ray
            crystal structure and the other from a Dreiding mode-based,
            computerassisted search.The pharmacological, structural and
            conformational observations strongly support the hypothesis that CCK
            and the ergopeptines share common sites of action in the CNS.
 CNR:
            5876426

 Author:
            Grandolini, G.; Tiralti, M. C.; Rossi, C.; Ambrogi, V.; Orzalesi, G.; Regis,
            M. De
 Reference:
            Journal, FRPSAX, Farmaco Ed.Sci., EN, 42, 1, 1987, 43-60
 Title:
            STUDIES ON ANNELATED 1,4-BENZOTHIAZINES AND
            1,5-BENZOTHIAZEPINES. II - Synthesis of new series of 1- or
            2-substituted 4H-s-triazolo<3,4-c>-1,4-benzothiazines and related
            compounds with potential CNS activity
 Abstract:
            New series of 1- or 2-substituted
            4H-s-triazolo<3,4-c>-1,4-benzothiazines have been prepared.The
            1-substituted products were obtained starting from
            3-hydrazino-2H-1,4-benzothiazine derivatives (III) by treatment with
            chloroacethyl chloride followed by cyclization of the resulting
            chloroacethylderivatives into the chloromethyltriazolobenzothiazines
            (IV a-e), which were then reacted with the appropriate amines to give
            the desired compounds (V a-n).Other 1-substituted compounds were
            prepared by ring closure of (III) with cyanogen bromide, affording
            1-amino-4H-s-triazolo<3,4-c>-1,4-benzothiazines (XI a-e).The
            2-substituted compounds (VIII) were prepared from
            2,4-dihydro-1H-s-triazolo<3,4-c>-1,4-benzothiazin-1-ones (VII),
            synthesized from (I) by reaction with ethyl carbazate.The aminoalkyl
            side chain was introduced into (VII) in two steps: first by treatment with
            1-bromo-3-chloropropane, then by refluxing the resulting product with
            the appropriate amine.Some 4H-tetrazolo<5,1-c>-1,4-benzothiazines
            (XII) were also synthesized from (III).Preliminary pharmacological data
            on the CNS activity of the synthesized tricyclic compounds are
            reported.
 CNR:
            5879885

 Author:
            Ono, H.; Morishita, S.; Kasuya, M.; Kobayashi, M.; Miyamoto, M.; et al.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 37, 4, 1987, 384-388
 Title:
            Comparison of the Effects of the New Anxiolytic Suriclone and Benzodiazepines on Motor Function and Electroencephalogram
 Abstract:
            (6-(7-Chloro-1,8-naphthyridin-2-yl)-7-oxo-2,3,6,7-tetrahydro-5H-1,4-dithiino<2,3-c>pyrrol-5-yl)-4-methyl-1-piperazinecarboxylate
            (suriclone, RP 31264), a new anxiolytic, produced behavioral effects similar to those of diazepam and lorazepam, had a
            protective effect against electroshock convulsion and potentiated the sleeping effect of hexobarbital in mice.It inhibited crossed
            extensor reflexes in chicks and augmented the dorsal root reflex potential, the increase of which is considered to be an index of
            increased GABAergic presynaptic inhibition.Suriclone produced high-amplitude slow waves in the amygdala and cerebral
            cortex and desynchronization of theta waves in the hyppocampus in rat electroencephalogram (EEG).These observations were
            quantitatively confirmed by power spectrum analysis of EEG.The mechanism of action of suriclone on the CNS are discussed
            in relation to those of benzodiazepines. - Keywords: Anxiolytics.Benzodiazepines.Diazepam, pharmacology.Lorazepam,
            pharmacology.RP 31264.Suriclone, pharmacology
 CNR:
            5880844

 Author:
            Singh, G. B.; Leach, G. D. H.; Atal, C. K.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 37, 1, 1987, 708-712
 Title:
            Pharmacological Actions and Acute Toxicity of Methyl- and
            Phenyl-3-methoxy-4-hydroxy Styryl Ketones
 Abstract:
            Some pharmacological actions and acute toxicity effects of methyl-
            and phenyl-3-methoxy-4-hydroxy styryl ketones have been described
            in experimental animals.The compounds antagonised the contractions
            evoked by a variety of agonists on several smooth muscle
            preparations in vitro.They produced inhibitory effects on spontaneously
            contracting uteri from pregnant rats and relaxant effects on pendular
            movements of rabbit duodenum and on dog intestinal movements in
            vivo.The compounds inhibited the castor oil induced diarrhoea in rat
            and propulsion of charcoal test meal in mice.Phenylbutazone showed
            similar effect on castor oil diarrhoea.The compounds failed to modify
            gestation period or parturition in pregnant rats.They antagonised
            bradykinin-induced bronchospasm in guinea pig.The compounds
            showed no significant effect on cardiovascular and respiratory
            systems; CNS and general behaviour were not affected even at high
            doses.Oral LD50 for both the compounds was greater than 2 g/kg. -
            Key words: Methyl-3-methoxy-4-hydroxy styryl ketone, pharmacology,
            toxicity .Phenyl-3-methoxy-4-hydroxy styryl ketone, pharmacology,
            toxicity
 CNR:
            5910953

 Author:
            Ferranti, A.; Garuti, L.; Giovanninetti, G.; Gaggi, R.; Roncada, P.; Nardi,
            P.
 Reference:
            Journal, FRPSAX, Farmaco Ed.Sci., IT, 42, 4, 1987, 237-250
 Title:
            PREPARAZIONE ED ATTIVITA ANALGESICA DI ALCUNE
            TETRAIDROCHINOLINE E TETRAIDROISOCHINOLINE
 Abstract:
            A series of 1,2,3,4-tetrahydroquinolines and of
            1,2,3,4-tetrahydroisoquinolines were synthesised and evaluated for
            analgesic activity by both hot-plate and acetic acid writhing methods in
            rats.The most potent compound was
            2-methyl-1,2,3,4-tetrahydro-5-quinolinol (IV i) which was shown to be
            1/8 and 1/50 as active as morphine according to the employed
            assay.The analgesic activity was shown to be associated to a not
            selective action on the CNS.
 CNR:
            5913723

 Author:
            Ambrogi, V.; Grandolini, G.; Rossi, C.; Tiralti, M. C.
 Reference:
            Journal, FRPSAX, Farmaco Ed.Sci., EN, 42, 8, 1987, 575-584
 Title:
            STUDIES ON ANNELATED 1,4-BENZOTHIAZINES AND
            1,5-BENZOTHIAZEPINES. III - Synthesis and CNS activity of some
            1-substituted derivatives of the novel heterocyclic system
            4,5-dihydro-s-triazolo <3,4-d>-1,5-benzothiazepine
 Abstract:
            A series of new 4,5-dihydro-s-triazolo <3,4-d>-1,5-benzothiazepines
            has been prepared.All the described compounds are representative of
            a novel ring system.Some of these compounds were tested for their
            CNS activity and effects comparable with the ones of diazepam were
            observed.
 CNR:
            5913741

 Author:
            Carenini, G.; Meglio, P. de; Gentili, P.; Manzardo, S.
 Reference:
            Journal, FRPSAX, Farmaco Ed.Sci., IT, 42, 11, 1987, 861-872
 Title:
            DERIVATI DELLA TRANS-1-(4-FENILCICLOESIL)ETILAMMINA AD
            ATTIVITA' ANTIDEPRESSIVA - II
 Abstract:
            Some derivatives of trans-1-(4-phenylcyclohexyl)ethylamine (A) with a
            substituent at position 4 of the phenyl group were prepared and tested
            for antireserpine activity on the CNS.All compounds showed reduced
            activity compared with that of (A) except the amino derivative (II) which
            proved more active but at the same time showed increased toxicity
            and other adverse effects on the CNS.
 CNR:
            5913761

 Author:
            Bhatia, Sangeeta; Kaushik, Narender K.; Sodhi, Gurvinder S.
 Reference:
            Journal, JRMPDM, J.Chem.Res.Miniprint, EN, 6, 1987, 1519-1536
 Title:
            Organomercury(II) Purines: Synthesis, Characterisation and Biological
            Studies of Organomercury(II) Theophylline and Theobromine
            Complexes
 Abstract:
            Organomercury(II) purine complexes of the type RHgL(I) and
            RHgCl(L1)(II)<L = phenyl (C6H5), o-hydroxyphenyl (o-HOC6H4),
            p-hydroxyphenyl (p-HOC6H4), p-acetoxyphenyl (p-AcOC6H4), 2-furyl
            (2-C4H3O); HL = theophylline, L1 = theobromine> have been
            synthesised and characterised.Conductance measurements indicate
            that the compounds are non-electrolytes.The bonding mode of the
            ligands to the metal has been ascertained by IR and UV spectral
            studies.The 1H and 13C NMR spectra confer with the stoichiometry of
            the complexes.Fluorescence studies have been carried out for the o-
            and p-HOC6H4HgL and for the o- and p-HOC6H4HgCl(L1)
            complexes.For the phenylmercury(II), p-hydroxyphenylmercury(II) and
            p-acetoxyphenylmercury(II) complexes, thermal studies (TG and DSC)
            have been carried out and various kinetic and thermodynamic
            parameters for thermal degradation have been enumerated.In addition,
            the fragmentation patterns of the complexes have been analysed on
            the basis of the mass spectra.Some representative complexes have
            been screened for CNS and antibacterial activity. <formula>(I),
            <formula>(II).
 CNR:
            5939953

 Author:
            Maryanoff, Bruce E.; McComsey, David F.; Gardocki, Joseph F.;
            Shank, Richard P.; Costanzo, Michael J.; et al.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 30, 8, 1987, 1433-1454
 Title:
            Pyrroloisoquinoline Antidepressants. 2. In-Depth Exploration of
            Structure-Activity Relationships
 Abstract:
            A series of pyrrolo<2,1-a>isoquinolines, and related compounds, were
            examined for antidepressant-like activity, by virtue of their antagonism
            of tetrabenazine-induced ptosis and sedation, and inhibition of
            biogenic amine uptake.Thus, we have identified some of the most
            potent antagonists of TBZ-induced ptosis and some of the most potent
            inhibitors of the uptake of dopamine, norepinephrine, and serotonin (in
            rat brain synaptosomes) ever reported.Compounds of particular note,
            in this regard, are 52b, 29b, 22b, and 48b, respectively.Biological
            activity was chiefly manifested by the trans isomeric class.Also,
            through resolution of four compounds, 7b, 24b, 37b, and 48b,
            biological activity was found to be associated with the (+) enantiomer
            subgroup (salts measured at 589 nm in MeOH), corresponding to the
            6S,10bR absolute configuration for 7b, 37b, and 48b, and the 6R,10bR
            configuration for 24b.An X-ray determination on (+)-24b*HBr
            established its absolute configuration; configurations for the other
            compounds were verified by enantiospecific synthesis starting with
            (+)-(R)-2-phenylpyrrolidine.Regarding the pendant phenyl ring, diverse
            substitution patterns were investigated.Those substitutions that were
            particularly unfavorable were 3',4',5'-trimethoxy (20b),
            2',3',4',5',6'-pentafluoro (34b), 2'-trifluoromethyl (38b),
            3',5'-bis(trifluoromethyl) (42b), 4'-n-butyl (44b), 2'-cyano (47b),
            4'-methylsulfonyl (50b), and 2'-carboxy (58b).Exceedingly potent
            compounds, in one way or another, were 10b-12b, 22b, 23b, 25b, 28b,
            29b, 33b, 45b, 48b, 51b-53b.The pattern of aromatic substitution had a
            strong impact on selectivity in the uptake tests (NE vs.DA vs.
            5-HT).Activity was significantly diminished by methyl substitution of 7b
            at the 5 (65, 66), 6 (61b), or 10b (60b) position, by changing the phenyl
            group of 7b to cyclohexyl (67b), benzyl (68b), or H (72), by moving the
            phenyl group of 7b to the 5 (69) or 10b (70) position, by expansion of
            ring B to an azepine (78b), and by modification of ring C to an azetidine
            (77b), piperidine (75b), or azepine (74b).The interaction of selected
            analogues with various CNS receptors is reported.Little affinity was
            shown for the muscarinic cholinergic receptor, suggesting a lack of
            anticholinergic side effects.Interestingly, 24b and 33b displayed a high
            affinity for the serotonin-2 receptor, analogous to mianserin and
            clomipramine.After the body of data was reviewed, derivatives 24b and
            48b were chosen for advanced development.
 CNR:
            5964411

 Author:
            Nagarajan, Kuppuswamy; David, Joy; Kulkarni, Yashwant S.; Hendi,
            Shivakumar B; Shenoy, Sharada J.; Upadhyaya, Pramod
 Reference:
            Journal, EJMCA5, Eur.J.Med.Chem.Chim.Ther., EN, 21, 1, 1986,
            21-26
 Title:
            Piperazinylbenzonaphthoxazepines with CNS depressant properties
 Abstract:
            The synthesis of six different types of benzonaphthoxazepine ring
            systems is described.Several derivatives of these ring systems were
            examined for their CNS effects, especially those, carrying a
            4-methyl-1-piperazinyl residue.Among these,
            13-(4-methyl-1-piperazinyl)benzo<b>naphth<1,2-f><1,4>oxazepine 32
            and
            13-(4-methyl-1-piperazinyl)benzo<b>naphth<2,3-f><1,4>oxazepine 45,
            were more potent than clozapine 3 in some tests, especially the one for
            antimescaline activity; however, these were inferior in antiaggression
            test in septal rats.Key-words: Neuroleptic agents -
            Piperazinylbenzonaphthoxazepines - Antimescaline activity
            antiaggression properties.
 CNR:
            5664809

 Author:
            Boudet-Dalbin, Raymond; Durand, Suzanne; Adam, Yves; Moreau,
            Robert C.; Foussard-Blanpin, Odette
 Reference:
            Journal, EJMCA5, Eur.J.Med.Chem.Chim.Ther., FR, 21, 2, 1986,
            131-137
 Title:
            Composes a groupe trimethoxyphenylsulfonyle III. - Synthese et
            activite pharmacologique de derives a groupe trimethoxy-2,3,4
            phenylsulphonyle
 Abstract:
            A new series of compounds having in common the
            2,3,4-trimethoxyphenylsulphonyl radical have been synthesized. 6
            Aminoalkylsulfones and 7 aminoalkylsulfonamides are tested on mice
            for a pharmacological study.Most of them are CNS depressants.The
            contribution of the side chain to activity is particularly studied.
            Key-words: Trimethoxyphenylsulfonyle - Psycholeptique - CNS.
 CNR:
            5665148

 Author:
            Boudet-Dalbin, Raymond; Grassy, Gerard; Adam, Yves; Moreau,
            Robert C.
 Reference:
            Journal, EJMCA5, Eur.J.Med.Chem.Chim.Ther., FR, 21, 3, 1986,
            205-212
 Title:
            Composes a groupe trimethoxyphenylsulfonyle. IV. Etude multivariee
            de l'activite et des relations structure-activite
 Abstract:
            The CNS depressive activity of the 30 compounds with the
            trimethoxyphenylsulfonyl radical have been previously
            presented.Some of their chemical, physical and structural properties
            are now summerized.Their pharmacological activity is studied by the
            mean of 3 multivariate analyses.Principal Component Analysis shows
            clearly the pharmacology of this series.Cluster Analysis divides the
            compounds into 2 sets : "active" and "less active".Step by step
            Discriminant Analysis applied to these 2 sets gives precise
            Structure-Activity Relations.
 CNR:
            5665444

 Author:
            Corelli, Federico; Massa, Silvio; Stefancich, Giorgio; Ortenzi, Giovanni;
            Artico, Marino; et al.
 Reference:
            Journal, EJMCA5, Eur.J.Med.Chem.Chim.Ther., EN, 21, 5, 1986,
            445-450
 Title:
            Benzodiazepines with both sedative and analgesic activities
 Abstract:
            The synthesis of
            5,6-dihydro-4H-pyrrolo<1,2-a><1,4>benzodiazepine-4-acetic acid is
            described.Aroylation of the ethyl ester of this acid and subsequent
            alkaline hydrolysis afforded the related 5-(4-chlorobenzoyl) and
            5-(4-methylbenzoyl) amides.The new acetic acids here reported have
            been submitted to pharmacological screening to assay both their
            antiinflammatory-analgesic activities and their
            neuropsychopharmacological effects.Key-words: Benzodiazepine
            derivatives - Pyrrolobenzodiazepines - Antiinflammatory agents -
            NSAIAs - CNS agents
 CNR:
            5667392

 Author:
            Tatee, Tochiro; Kurashige, Shuji; Shiozawa, Akira; Narita, Kazuhisa;
            Takei, Masao; et al.
 Reference:
            Journal, CPBTAL, Chem.Pharm.Bull., EN, 34, 4, 1986, 1634-1642
 Title:
            Isoxazole Derivatives as Centrally Acting Muscle Relaxants. I.
            Synthesis and Activity of 5-(3-Aminopropyl)amino-3-phenylisoxazole
            Derivatives
 Abstract:
            A series of 5-amino-3-phenylisoxazole derivatives was synthesized
            and evaluated as part of a search for new types of centrally acting
            muscle relaxants.The derivatives with an alkylaminopropyl moiety
            exhibited muscle relaxant activity comparable to that of tolperisone (1),
            but this activity was accompanied by strong general central nervous
            system (CNS) depressant and slight anticonvulsant activities.On the
            other hand, the derivative with a propanamide moiety exhibited a
            favorable pharmacological profile for a selective muscle relaxant with
            little CNS depressant action.Keywords - isoxazole derivative; muscle
            relaxant; propanamide; anticonvulsant; tolperisone; anemic
            decerebrate rigidity; propylenediamine; traction test; motor activity;
            optical resolution
 CNR:
            5681285

 Author:
            Lipkowitz, Kenny; Burkett, Anthony; Landwer, Jo
 Reference:
            Journal, HTCYAM, Heterocycles, EN, 24, 10, 1986, 2757-2770
 Title:
            THEORETICAL STUDIES OF PSYCHOTROPIC DRUGS.
            QUESTIONING THE IMPORTANCE OF FLEX-ANGLE IN DRUG
            EFFICACY
 Abstract:
            MNDO calculations indicate that hetero-substituted
            9,10-dihydroanthracenes are inherently planar molecules.Ring
            puckering is a very low energy process that can arise from
            intramolecular effects, e.g. peri-and/or transannular interactions as well
            as from intermolecular interactions like crystal packing forces.It is
            concluded that the angle of flexure, determined crystallographically
            and used as a descriptor of drug activity in several important CNS
            drugs, should be used with caution or not be used at all.
 CNR:
            5698710

 Author:
            Lloyd, Edward J.; Andrews, Peter R.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 29, 4, 1986, 453-462
 Title:
            A Common Structural Model for Central Nervous System Drugs and
            Their Receptors
 Abstract:
            On the basis of the hypotesis that there is a common structural basis
            for central nervous system (CNS) drug action consisting primarily of an
            aromatic group and a nitrogen atom, a four-point model for a common
            pharmacophore is defined with use of five semirigid CNS-active drug
            molecules: morphine, strychnine, LSD, apomorphine, and
            mianserin.Two of the points of the model represent possible
            hydrophobic interactions between the aromatic group and the receptor,
            while the other two represent hydrogen binding between the nitrogen
            atom and the receptor.The model is then extended by the inclusion of
            nine additional CNS-active drug molecules: phenobarbitone,
            clonidine, diazepam, bicuculline, diphenylhydantoin, amphetamine,
            imipramine, chlorpromazine, and procyclidine, each being chosen as a
            key representative of a different CNS-active drug class or
            neurotransmitter system.Consideration of all phenyl group and
            nitrogen atom combinations, as well as all feasible conformations,
            shows that all nine molecules closely fit the common model in
            low-energy conformations.It is proposed that the model may eventually
            be used to design CNS-active drugs by mapping the relative locations
            of secondary binding sites.It can also be used to predict whether a
            given structure is likely to show CNS activity: a search over 1000
            entries in the Merck Index shows a high probability of CNS activity in
            compounds fitting the common structural model.
 CNR:
            5699022

 Author:
            Bhandari, K.; Murti, V. Aruna; Anand, Nitya
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 25, 1986, 1231-1233
 Title:
            Agents Acting on CNS: Part XXXIV -
            1,2,3,4,4a,5,6,7-Octahydropyrazino<1,2-a>-1-benzazepines
 Abstract:
            3-Substituted
            1,2,3,4,4a,5,6,7-octahydropyrazino<1,2-a>-1-benzazepines (II) have
            been synthesized starting from
            2-methylthio-4,5-dihydro-3H-1-benzazepine (III).Some 2-substituted
            aminoalkyl-2,3,4,5-tetrahydro-1H-1-benzazepines (IX) have also been
            synthesized by condensing
            2-aminoalkyl-2,3,4,5-tetrahydro-1H-1-benzazepines (V) with different
            aldehydes followed by LAH reduction of the Schiff bases.None of these
            compounds exhibits any noteworthy pharmacological activity.
 CNR:
            5703605

 Author:
            Mohan, Rajiv Ravindra; Agarwal, Rajesh; Misra, V. S.
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 25, 1986, 1234-1237
 Title:
            Synthesis of 2/9-Substituted Indophenazin-6-acetic Acid
            a-Aryl/methylbenzylidenehydrazides,
            4-Aryl-1-(indophenazin-6-methylcarbonyl)-3-thiosemicarbazides and
            6-(4-Aryl-5-mercapto-4H-1,2,4-triazol-3-ylmethyl)indophenazines as
            CNS Active and
 Abstract:
            2/9-Substituted indophenazine-6-acetic acid
            a-aryl/methylbenzylidenehydrazides (IVa-l) and
            4-aryl-1-(2/9-substituted
            indophenazin-6-methylcarbonyl)-3-thiosemicarbazides (Va-j) have
            been synthesised by condensing 2/9-substituted
            indophenazin-6-acetic acid hydrazides (III) with different aryl
            aldehydes/acetophenones and phenyl isothiocyanates, respectively.All
            the thiosemicarbazides (V) undergo cyclisation in 2N NaOH to give
            2/9-substituted
            6-(4-aryl-5-mercapto-4H-1,2,4-triazol-3-ylmethyl)indophenazines
            (VIa-j).All these compounds have been found to be nontoxic and CNS
            active.Most of them show significant protection against
            carrageenin-induced inflammation.
 CNR:
            5703606

 Author:
            Mohan, Rajiv Ravindra; Agarwal, Chapla; Misra, V. S.
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 25, 1986, 339-341
 Title:
            Synthesis of Some Newer
            4-(3-Methyl-5-oxo-4-pyrazolidenemethyl)phenoxyacetic Acid
            Benzylidenehydrazides and a-Methylbenzylidenehydrazides as CNS
            Active and Antiinflammatory Agents
 Abstract:
            The title compounds (IVa-q) have been synthesized and found to be
            non-toxic and CNS depressant or stimulant.In antiinflammatory
            activity, these compounds show 4-23percent protection against the
            carrageenin-induced mice paw oedema.
 CNR:
            5703635

 Author:
            Husain, M. I.; Shukla, Sarveshwar
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 25, 1986, 545-548
 Title:
            Synthesis and Biological Activities of
            3-(2'-Aryl-4'-oxothiazolidin-3'-yl)-2-phenylquinazolin-4(3H)-ones
 Abstract:
            A number of
            3-(2'-aryl-4'-oxothiazolidin-3'-yl)-2-phenyl-quinazolin-4(3H)-ones (III)
            have been synthesised and screened for their possible antibacterial
            activity and CNS activity on albino mice.Some chemical leads towards
            structure-activity relationship have been established.
 CNR:
            5703744

 Author:
            Shridhar, D. R.; Sastry, C. V. Reddy; Bansal, O. P.; Rao, P. Pulla
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 25, 1986, 874-876
 Title:
            Synthesis and Biological Activity of Some New N-(2H-1,4-benzoxazin-
            and benzothiazin-3-yl)-N'-arylureas
 Abstract:
            A series of new N-(2H-1,4-benzoxazin- and
            benzothiazin-3-yl)-N'-arylureas (IV) and
            N-(4-methyl-2H-1,4-benzothiazinylidin-3-yl)-N'-arylureas (V) have been
            synthesised and screened for antiinflammatory, CNS, anthelmintic,
            antiprotozoal and antimicrobial activities.Some of the compounds
            possess a low order of antiinflammatory and mild CNS depressant
            activities.
 CNR:
            5704092

 Author:
            Rao, Ch. Bheemasankara; Raju, G. V. Subba; Raju, P. V. Narasimha
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 25, 1986, 400-403
 Title:
            Studies on Pyrazolines: Syntheses, Pyrolysis and Reactivity of Some
            3-Aroyl-4-aryl-D2-pyrazolines
 Abstract:
            D2-Pyrazolines (IIb-i)have been obtained through cycloaddition of
            diazomethane to chalcones (Ib-i).The structure (II) has been firmed
            established on the basis of PMR and (13)C NMR data.Pyrolysis and
            chemical reactivity of II are described.These compounds exhibit mild
            local anaesthetic, CNS depressant and anticonvulsant activities.
 CNR:
            5704104

 Author:
            Sidahmed, Ibrahim M.; Wells, Cecil F.
 Reference:
            Journal, JCFTAR, J.Chem.Soc.Faraday Trans.1, EN, 82, 1986,
            2577-2588
 Title:
            Ionic Solvation in Water-Cosolvent Mixtures. Part 12. - Free Energies
            of Transfer of Single Ions from Water into Water-Propan-1-ol Mixtures
 Abstract:
            The spectrophotometric solvent-sorting method for determining the
            free energy of transfer of the solvated proton, DG0t(H(1+)), between
            water and mixtures of water-cosolvent has been applied to mixtures of
            water with propan-1-ol.The assumptions underlying the method are
            examined critically and the consequences of varying the standard
            states of the species involved in the solvent sorting in the mixture are
            explored.The resulting values for DG0t(H(1+)) are used to determine
            DG0t(X(1-)) from DG0t(HX) and these values for DG0t(X(1-)) are used
            to determine DG0t(M(1+)) for other cations from DG0t(MX).The variation
            of DG0t(i) for individual ions in water-propan-1-ol are compared with
            the variation of DG0t(i) in mixtures of water with other
            cosolvents.Values for DG0t(Ag(1+)) and DG0(CNS(1-)) are determined
            for other water-cosolvent mixtures.
 CNR:
            5720000

 Author:
            Raisi, A.; Beckett, A.H.
 Reference:
            Journal, MOCMB7, Monatsh.Chem., EN, 117, 1986, 1047-1056
 Title:
            Identification and Quantitative Analysis of Phendimetrazine and Some
            of its Metabolites in Biological Fluids
 Abstract:
            In urine, after oral doses of phendimetrazine to man, were found
            unchanged drug, the N-demethylated metabolite, phenmetrazine, and
            the N-oxide of phendimetrazine, but not N-hydroxyphenmetrazine; the
            metabolites were identified using t.l.c. and g.l.c.The stability of the drug
            and its metabolites in biological fluids and in ether was studied.A gas
            chromatographic procedure for the quantitative determination of
            unchanged drug, its N-oxide and phenmetrazine in urine, plasma and
            saliva was developed, the N-oxide being reduced before analysis. -
            Keywords: Amphetamins; Anorectics; Antiobesity; CNS stimulants;
            Phendimetrazine
 CNR:
            5734643

 Author:
            Szirtes, Tamas; Kisfaludy, Lajos; Palosi, Eva; Szporny, Laszlo
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 29, 9, 1986, 1654-1658
 Title:
            Synthesis of Thyrotropin-Releasing Hormone Analogues. 2.
            Tripeptides Structurally Greatly Differing from TRH with High Central
            Nervous System Activity
 Abstract:
            A new series of thyrotropin-releasing hormone (TRH) analogues,
            obtained by further modifications of our most potent central nervous
            system (CNS) stimulating neutral tripeptides at both termini, were
            synthesized by the pentafluorophenyl ester method and tested for CNS
            and thyrotropin (TSH) releasing activity.Replacement of pyroglutamic
            acid by pyro-2-aminoadipic acid, 2-oxoimidazolidine-4-carboxylic acid
            or g-butyrolactone-g-carboxylic acid and that of proline by pipecolic
            acid, thiazolidine-4-carboxylic acid, or homoproline in <Leu2>- and
            <Nva2>TRH led to tripeptides structurally widely different from TRH.In
            spite of this fact, 7 of the 17 analogues (1, 2, 8-10, 16, and 17) have
            stronger anticataleptic effect than TRH, with negligible or no hormonal
            potency.The highest CNS activity was achieved when pyroglutamic
            acid was replaced by pyro-2-aminoadipic acid at the N-terminus
            <pAad-Leu-Pro-NH2, 1 (RGH 2202), and pAad-Nva-Pro-NH2, 2>.A
            novel synthesis of L-2-aminoadipic acid suitable for large-scale
            preparation is also described.
 CNR:
            5746075

 Author:
            Shridhar, D. R.; Sastry, C. V. Reddy; Lal, B.
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 25, 1986, 986-988
 Title:
            Antiinflammatory Agents: Part IX - Synthesis of Some New
            2H-1,4-Benzoxazin-3-yl-aminophenyl-alkanoic Acid Esters
 Abstract:
            Some new methyl
            4-<(substituted-2H-1,4-benzoxazin-3-yl)amino>-phenylalkanoates (5
            and 6) and the corresponding p-chlorobenzoyl derivatives (7 and 8)
            have been prepared and screened for their CNS and antiinflammatory
            activities.
 CNR:
            5749942

 Author:
            Dlugosz, Anna; Machon, Zdzislaw
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), EN, 319, 2, 1986,
            102-108
 Title:
            Syntheses of Potentially Active 1-Substituted
            Imidazo<1,2-c>pyrimidine Derivatives
 Abstract:
            A series of 1-substituted
            7-methyl-2,3-dihydroimidazo<1,2-c>pyrimidin-5-ones has been
            obtained by treatment of
            2-hydroxy-4-mercapto-6-methyl-5-pyrimidinecarboxylic acid (1) with
            aminoalcohols followed by chlorination, cyclization and
            alkylation.Some of the obtained imidazo<1,2-c>pyrimidine derivatives
            were CNS active and showed antiinflammatory activity.
 CNR:
            5776635

 Author:
            Harting, J.; Becker, K. H.; Bergmann, R.; Bourgois, R.; Enenkel, H. J.; et al.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 36, 2, 1986, 200-208
 Title:
            Pharmacodynamic Profile of the Selective b1-Adrenoceptor Antagonist Bisoprolol
 Abstract:
            The pharmacodynamic activity of
            (+/-)-1-<4-(2-isopropoxyethoxymethyl)-phenoxy>-3-isopropylamino-2-propanol-hemifumarate
            (bisoprolol, EMD 33 512) has been investigated under in vitro and in vivo
            conditions.Bisoprolol was found to be an effective b-adrenoceptor antagonist, the pA2 values
            determined against isoprenaline in guinea pig atria and tracheal muscle being 7.45 and 6.41,
            respectively.Thus, the selectivity ratio of bisoprolol in favour of b1-adrenoceptors is
            11.Inhibition of the isoprenaline-induced tachycardia in guinea pigs indicated a long duration
            of action for bisoprolol.The compound was devoid of intrinsic sympathomimetic activity as
            shown by the lack of effect on heart rate in anaesthetized and reserpine pretreated
            rats.Studies in rabbits and guinea pigs revealed a local anaesthetic activity of bisoprolol at
            high concentrations.Bisoprolol protected the hearts of anaesthetized dogs against the
            sequelae of intermittent coronary occlusions, as judged by the reduction of the ST-segment
            elevation in the epicardial ECG.Bisoprolol exerted a blood pressure lowering effect in
            conscious renal hypertensive dogs after oral administration of 30 mg/kg.There was no
            indication of any action on the CNS in monkeys following an oral dose of up to 8 mg/kg. - Key
            words: Atenolol; b-Blockers; Bisoprolol, b1-selectivity, pharmacodynamics; EMD 33 512;
            Metoprolol; Procaine; Practolol; Propranolol
 CNR:
            5793594

 Author:
            Bechtel, W. D.; Mierau, J.; Pelzer, H.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 36, 5, 1986, 793-796
 Title:
            Biochemical Pharmacology of Pirenzepine. Similarities with tricyclic antidepressants in
            antimuscarinic effects only
 Abstract:
            5,11-Dihydro-11-<(4-methyl-1-piperazinyl)acetyl>-6H-pyrido<2,3-b><-1,4>-benzodiazepin-6-one
            dihydrochloride (pirenzepine, Gastrozepin) and some tricyclic antidepressant drugs which show
            a very close relationship concerning the chemical structure were investigated in numerous
            binding, uptake and enzymatic studies in vitro.With pirenzepine a high affinity binding could be
            demonstrated only to muscarinic receptors (Ki = 58 nmol/l).In all other studies pirenzepine had a
            very weak or no effect at all.In contrast, tricyclic antidepressants bound with high but different
            affinities to various receptors as known from numerous publications.The highest affinities were
            found with imipramine at the specific imipramine binding sites (Ki = 9.8 nmol/l), and at the
            a1-receptor (Ki = 39 nmol/l), with desipramine at the muscarinic receptors (Ki = 88 nmol/l), with
            mianserin at the H1-(Ki = 3.4 nmol/l) and 5HT2-receptors (Ki = 7.3 nmol/l).Moreover, imipramine
            and desipramine showed their known substantial inhibition of noradrenaline and/or
            5-hydroxytryptamine uptake.Thus, a homogeneous affinity or activity profile of the
            antidepressants studies does not exist.The only common property of pirenzepine and the
            tricyclic antidepressants was found to be the high affinity binding to the muscarinic receptors
            which might explain the common antisecretory action of these agents.Because of the unique
            specificity of pirenzepine lacking all other effects of the tricyclic antidepressants as
            demonstrated in this study, it is very unlikely that this drug exerts any antidepressant-like central
            action. - Key words: Antidepressants, tri- and tetracyclic; CNS receptors; Gastric acid secretion;
            Gastrozepin; MAO inhibitors; Pirenzepine, biochemical pharmacology
 CNR:
            5795083

 Author:
            Carlo, P.; Maura, A.; Ledda, A.; Finollo, R.; Ricci, R.; Brambilla, G.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 36, 5, 1986, 797-800
 Title:
            Lack of DNA Fragmentation in Rats Treated with High Oral Doses of
            Drugs Acting on the Central Nervous System
 Abstract:
            Five drugs acting on the central nervous system - chlorpromazine,
            triflupromazine, thioridazine, chlordiazepoxide, and ethosuximide -
            which provided conflicting results in previous genotoxicity assays have
            been tested for their DNA-damaging activity in vivo.The capability of
            these drugs of inducing DNA fragmentation was investigated by the
            use of two different techniques: rate of DNA strand separation in alkali
            as measured by hydroxylapatite chromatography, and changes of DNA
            viscometric behavior as detected by a new highly sensitive
            method.DNA damage, as checked by the first technique, was absent in
            both liver and gastric mucosa of rats given a single p.o. administration
            of 1/2 LD 50 of the drugs.These negative results were confirmed by the
            subsequent viscometric analysis of liver DNA from rats treated with the
            same doses. - Key words: Chlordiazepoxide; Chlorpromazine;
            CNS-active drugs; DNA fragmentation; Ethosuximide; Thioridazine;
            Triflupromazine
 CNR:
            5795084

 Author:
            Moratalla, R.; Romera, R.; Galiano, A.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 36, 6, 1986, 918-923
 Title:
            Pharmacological Study of the New Mucolytic Drug N-Guanyl-cysteine
 Abstract:
            The pharmacological evaluation of N-guanyl-cysteine (IQB-782) is
            reported.This new cysteine derivative shows a potent
            mucolytic-expectorant activity in different test systems.Thus, IQB-782
            protects rats against tobacco-smoke-induced respiratory airway
            obstruction, increases the tracheo-bronchial mucus secretion in rabbits
            and increases the pulmonary excretion of fluorescein in mice, an index
            of bronchosecretogogue activity.Like other mucolytics, IQB-782 is also
            effective in vitro in reducing the viscosity of a suspension of gastric
            mucin.This new drug is apparently devoid of any cardiovascular or
            autonomic activity and shows a moderate CNS depressant
            effect.IQB-782 is consequently a new thiol derivative which may offer
            some advantages in the treatment of different types of obstructive
            pulmonary disease. - Key words: Bronchosecretogogues;
            N-Guanyl-cysteine, pharmacology; IQB-782; Mucolytics
 CNR:
            5795286

 Author:
            Fantuz, M.; Bertoli, D.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 36, 9, 1986, 1366-1368
 Title:
            General Pharmacological Properties of a Low Molecular Weight
            Heparin in Rodents
 Abstract:
            The effects on central nervous system of a new low molecular weight
            heparin (OP/LMWH) were studied in mice and rats.The effect of
            OP/LMWH on respiration, blood pressure and heart rate was studied in
            guinea-pigs and rats.In these studies unfractionated heparin was used
            for comparison.OP/LMWH, up to 10 mg/kg/s.c., did not show any effect
            on central nervous system and did not increase the blood pressure,
            heart rate and respiration rate up to 10 mg/kg i.v.At the same dosages,
            heparin presented effects similar to those shown by OP/LMWH. - Key
            words: Antithrombotic drugs; Heparin, CNS effects, low molecular
            weight, pharmacology, unfractionated; Low molecular weight heparin
 CNR:
            5795968

 Author:
            Krieglstein, J.; Heuer, H.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., GE, 36, 11, 1986, 1568-1571
 Title:
            On the Usefulness of a Model of Acute Hypoxia for Testing
            Cerebroprotective Drugs
 Abstract:
            The aim of this study was to find out whether the mouse in acute
            normobaric hypoxia (3.5percent O2) may be appropriate as a
            screening model for testing cerebroprotective drugs.The survival time
            of the mice in hypoxia was used to determine drug effects. 39 agents
            with various pharmacological and toxicological properties were
            investigated.Cerebroprotective, centrally depressant and stimulating
            as well as cardiovascular drugs were included.Only 6 out of 16
            cerebroprotective drugs used therapeutically prolonged the survival
            time of mice in acute hypoxia.However, a positive effec t was
            demonstrable especially for those cerebroprotective drugs (extractum
            Ginkgo bilobae, meclofenoxate, naftidrofuryl, pentoxifylline and
            pyritinol), which are generally accepted to be active.On the other hand,
            12 out of 23 drugs which are therapeutically used as cardiovascular
            drugs, central stimulants or depressants or have known toxicological
            effects also prolonged the survival time of mice in hypoxia.Thus, it
            became clear that the result of this hypoxia test may be influenced by
            various pharmacological actions.Especially drugs stimulating the
            cardiovascular system or depressing CNS activity could prolong the
            survival time of mice in hypoxia, whereas drugs with vasodilating
            effects could even shorten it.Opposite effects could superpose or
            neutralize each other.Therefore, the mouse in acute hypoxia seems to
            be of limited value as a screening model for testing cerebroprotective
            drugs. - Key words: Acute hypoxia, screening model;
            Cerebroprotective drugs; Nootropics
 CNR:
            5796735

 Author:
            Ferrini, R.; Miragoli, G.; Sala, R.; Reggiani, A.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 36, 2a, 1986, 327-330
 Title:
            Activity of Ibopamine on Central Nervous System in Mice and Rats
 Abstract:
            Ibopamine (SB-7505), the 3,4-diisobutyryl ester of N-methyldopamine
            has proved to be able to induce cardiovascular and renal effects after
            oral administration which were comparable to those of dopamine
            injected intravenously.In the present paper ibopamine was
            investigated on some behavioural, motility and biochemical tests with
            a view to assaying its possible activity on the central nervous system
            (CNS).The results obtained show that ibopamine has no significant
            activity on CNS. - Key words: Central nervous system; Dopamine;
            Dopaminergic agonists; Epinine; Ibopamine,pharmacology;
            N-Methyldopamine; SB-7505
 CNR:
            5834550

 Author:
            Villani, F. J.; Magatti, C. V.; Vashi, D. B.; Wong, J.; Popper, T. L.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 36, 9, 1986, 1311-1314
 Title:
            N-Substituted
            11-(4-Piperidylene)-5,6-dihydro-11H-benzo<5,6>cyclohepta<1,2-b>pyridines.
            Antihistamines with no sedating liability
 Abstract:
            Conversion of the basic tertiary amino function of the potent antihistamine,
            azatadine (Optimine), to neutral carbamate function results in compounds
            which retain significant antihistamine activity with little or no CNS effects.In
            guinea pigs the N-ethoxycarbonyl derivative 4 had the same antihistamine
            potency as terfenadine, a clinically used non-sedating antihistamine.In mice,
            4 was a potent antihistamine while lacking CNS effects.The
            8-chloro-N-ethoxycarbonyl 5 (loratadine, Sch 29851) was the most potent
            antihistamine in the series, had no CNS side effects, and was selected for
            clinical evaluation. - Key words: Antihistamines, lack of sedating liability;
            Azatadine; Loratadine; Optimine; Piperidylene carbamates, pharmacology,
            synthesis, tricyclic; Sch 29851
 CNR:
            5834826

 Author:
            Yevich, Joseph P.; New, James S.; Smith, David W.; Lobeck, Walter
            G.; Catt, John D.; et al.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 29, 3, 1986, 359-369
 Title:
            Synthesis and Biological Evaluation of 1-(1,2-Benzisothiazol-3-yl)- and
            (1,2-Benzisoxazol-3-yl)piperazine Derivatives as Potential
            Antipsychotic Agents
 Abstract:
            Members of the series of title compounds were tested for potential
            antipsychotic activity in relevant receptor binding assays and
            behavioral screens.Structure-activity relationships within the series are
            discussed.Compound 24 (BMY 13859-1), a
            (1,2-benzisothiazol-3-yl)piperazine derivative, was selected for further
            study because of its potent and selective profile in primary CNS tests.It
            was active in the Sidman avoidance paradigm and blocked
            amphetamine-induced stereotyped behavior in dogs for up to 7 h.The
            compound's lack of typical neuroleptic-like effects in therat catalepsy
            test and its failure to produce dopamine receptor supersensitivity
            following chronic administration indicate that it should not cause the
            movement disorders commonly associated with antipsychotic
            therapy.Although 24 has potent affinity for dopaminergic binding sites,
            its even greater affinity for serotonin receptors suggests that a
            serotonergic component may be relevant to its atypical
            profile.Compound 24 is currently undergoing clinical evaluation in
            schizophrenic patients.
 CNR:
            5840654

 Author:
            Davies, M. K.; McAinsh, J.
 Reference:
            Journal, JPPMAB, J.Pharm.Pharmacol., EN, 38, 1986, 316-319
 Title:
            Tissue atenolol levels following chronic b-adrenoceptor blockade
            using oral atenolol in dogs
 Abstract:
            Tissue atenolol concentrations are high following chronic continuous
            b-adrenoceptor blockade in dogs.Furthermore, significant
            concentrations of this poorly lipid soluble drug are found within the
            central nervous system after chronic dosing.It is suggested that all
            b-adrenoceptor blocking agents may enter the central nervous system
            in significant and sufficient quantities to account for a central
            antihypertensive action of this group of compounds.Sequestration of
            b-adrenoceptor agents in the CNS or other tissues may account for
            other clinically observed effects including adaptive effects.
 CNR:
            5881923

 Author:
            Leung, Louis Y.; Baillie, Thomas A.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 29, 11, 1986, 2396-2399
 Title:
            Comparative Pharmacology in the Rat of Ketamine and Its Two
            Principal Metabolites, Norketamine and (Z)-6-Hydroxynorketamine
 Abstract:
            (Z)-6-Hydroxynorketamine (3), a secondary metabolite of the
            dissociative anesthetic agent ketamine (1), was synthesized, and its
            central nervous system (CNS) properties were compared to those of
            the parent drug and the primary metabolite, norketamine
            (2).Administration of compounds 1 and 2 to rats (40 mg/kg iv) produced
            general anesthesia and also led to marked increases in spontaneous
            locomotor activity during the postanesthetic recovery phase.These
            effects were of significantly longer duration with 1 than with 2.In
            contrast, the same dose of 3 produced neither general anesthesia nor
            CNS excitation, despite the fact that 3 entered brain tissue readily from
            the systemic circulation.It is concluded that the CNS effects of 1 are
            attenuated by metabolism to 2 and are abolished by subsequent
            hydroxylation to produce 3.Moreover, the results suggest that the
            desirable anesthetic properties of 1 and related arylcyclohexylamines
            may be inseparable from their ability to produce adverse
            postanesthetic emergence reactions.
 CNR:
            5890123

 Author:
            Arblaster, C. I.; Cameron, D. W.; Laycock, G. M.; Shulman, A.
 Reference:
            Journal, FRPSAX, Farmaco Ed.Sci., EN, 41, 1, 1986, 3-22
 Title:
            STUDIES ON THE DEVELOPMENT OF PHYSICAL DEPENDENCE
            ON BARBITONE IN THE RAT AND RAT ATRIUM
 Abstract:
            The mechanisms underlying the development of barbitone
            dependence have been studied in the rat and in atrial preparations
            removed from dependent animals.Long-term oral administration to the
            rat of barbitone, alone or together with the analeptics demegride or
            pentylenetetrazol, has shown that the intensity of the withdrawal
            syndrome generally parallels the degree of associated CNS
            depression.In addition, the overall relationship between the
            spontaneous or evoked (chemical or audiogenic) responses of
            representative drug-withdrawn rats and the inotropic responses of
            corresponding withdrawn atria to supramaximal nerve stimulation,
            noradrenaline or Ca2+ was reasonably good.It is proposed that the rat
            atrial preparation may provide a suitable model system for the study of
            barbitone dependence in the rat, especially in relation to
            Ca2+-dependent mechanisms, and that selective calcium antagonists
            may prove helpful in the management of barbiturate and similar types
            of drug dependence.The barbitone withdrawal syndrome has been
            described in terms of a membrane phase distribution hypothesis of
            drug action.
 CNR:
            5913762

 Author:
            Trabucchi, M.; Govoni, S.; Battaini, F.
 Reference:
            Journal, FRPSAX, Farmaco Ed.Sci., EN, 41, 4, 1986, 323-334
 Title:
            CHANGES IN THE INTERACTION BETWEEN CNS CHOLINERGIC
            AND DOPAMINERGIC NEURONS INDUCED BY
            L-a-GLYCERYLPHOSPHORYLCHOLINE, A CHOLINOMIMETIC
            DRUG
 Abstract:
            The present study investigates the cholinomimetic properties of the
            drug L-a-glycerylphosphorylcholine (a-GPC) at CNS
            level.Experiments using tritium labelled a-GPC indicate that the drug
            reaches the brain after i.p. and per os administration.In order to study
            the cholinomimetic properties of this drug an indirect functional index
            of cholinergic activation was used.In fact cholinergic agonists induce
            an activation of striatal dopaminergic output. a-GPC both i.p. and per
            os administered increased striatal dihydroxyphenylacetic acid
            (DOPAC) content.In addition, the in vitro K+ stimulated dopamine
            release was increased in rats treated in vivo with a-GPC.Since a-GPC
            has a weak displacing activity in QNB binding, the in vivo cholinergic
            activity might be due to the fact that this drug may increase the
            availability of choline for acetylcholine synthesis leading to increased
            acetylcholine production.This activity may be useful in those situations
            such as aging in which cholinergic activity is deficient.
 CNR:
            5913784

 Author:
            Cunningham, B.A.; Lis, L.J.; Quinn, P. J.
 Reference:
            Journal, MCLCA5, Mol.Cryst.Liq.Cryst., EN, 141, 1986, 361-368
 Title:
            The Influence of Monovalent Anions on
            Dipalmitoylphosphatidylcholine Bilayer Phase Transitions: A Time
            Resolved X-Ray Diffraction Study
 Abstract:
            The effect of monovalent anions on the packing structures and
            transitions of the lamellar phases of dipalmitoylphosphatidylcholine
            bilayers has been investigated at the Daresbury Synchrotron
            Laboratory (U.K.).Fully hydrated DPPC bilayers in the presence of 1M
            KBr swell past the usual repeat spacing observed in water by
            approximately 20 Angstroem and in the presence of 1M KSCN form an
            interdigitated gel phase.The transition temperatures, determined by
            changes in the bilayer parameters in the small and wide angle
            scattering profiles, occur at temperatures previously observed.Our
            observations also indicate that the changes in the bilayer unit cell
            produced by the presence of Br or CNS- do not change the nature of
            the phase transition.
 CNR:
            5920628

 Author:
            Mahesh, V. K.; Maheswari, Mamta; Sharma, Rakesh; Sharma, Rashmi
 Reference:
            Journal, CJCHAG, Can.J.Chem., EN, 63, 1985, 632-635
 Title:
            Analogs of cannabinoids: synthesis of some 7H-indolo-, 5H-imidazolo,
            7H-benzimidazolo<1,2-c> <1,3>benzoxazines - novel ring systems
 Abstract:
            Tetrahydrocannabinol 1, the active constituent of Cannabis sativa Linn,
            is a well-known CNS-active compound and introduction of a nitrogen
            atom at the ring junction of the pyran and alicyclic ring is of
            considerable interest.This prompted the synthesis of 7H-indolo<1,2-c>
            <1,3>-, 5H-imidazolo<1,2-c> <1,3>-, and 7H-benzimidazolo<1,2-c>
            <1,3>-benzoxazine, a novel heterocyclic system. 2-(2'-Hydroxyphenyl)
            indoles, 2-(2'-hydroxyphenyl) imidazoles, and 2-(2'-hydroxyphenyl)
            benzimidazoles are suitable intermediates for the preparation of this
            type of benzoxazines, as the second heterocycle (ring B) can then be
            constructed by introduction of a methylene bridge between the
            hydroxyl of the 2'-hydroxy phenyl substituent and the imino group of
            the heterocyclic system.
 CNR:
            5682070

 Author:
            Bien, E.; Gebert, I.; Skorka, G.; Thur, K.; Witt, M.
 Reference:
            Journal, PHARAT, Pharmazie, EN, 40, 6, 1985, 412-414
 Title:
            Biphasic Effect of Pyrazolone Derivatives on Drug-metabolizing
            Enzymes in Rat Liver
 Abstract:
            The pyrazolone derivatives aminophenazone, phenazone, and
            propylphenazone known as inducers are capable of inhibiting initially
            monooxygenase-dependent biotransformation steps.In the dose of 1.5
            mmol*kg-1 they prolong the hexobarbital narcosis (max. 1 h after
            administration) due to a reduced hexobarbital metabolism in the
            liver.An influence on the N-demethylation (aminophenazone as
            substrate) is not substantial.The catalytic binding site of cytochrome
            P-450 is not influenced.In aminophenazone- and phenazone-treated
            animals the inhibitory phase is followed by a stim ulatory one.After the
            repeated administration the inhibitory phase continues up to the third d
            measured 1 h after administration.The initially inhibitory effect of
            inducers seems to be caused by a mutual interference of a complete or
            partial binding to various forms of cytochrome P-450.However, effects
            on the CNS cannot be excluded.
 CNR:
            5689092

 Author:
            Weinhardt, Klaus; Wallach, Marshall B.; Marx, Michael
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 28, 6, 1985, 694-698
 Title:
            Synthesis and Antidepressant Profiles of Phenyl-Substituted 2-Amino-
            and 2-<(Alkoxycarbonyl)amino>-1,4,5,6-tetrahydropyrimidines
 Abstract:
            A series of 4(6)- and 5-phenyl-substituted 2-amino- and
            2-<(alkoxycarbonyl)amino-1,4,5,6-tetrahydropyrimidines 2 were
            prepared and evaluated for central nervous system (CNS) effects in
            animal models.Several 5-phenyl-substituted compounds possessed
            potent antidepressant activity and all compounds in this series were
            devoid of significant activity in any of the other CNS (anticolvunsant,
            muscle relaxant, and depressant) assays.The most active compound
            in the in vivo screen for antidepressant activity (reversal of
            reserpine-induced hypothermia),
            2-<(methoxycarbonyl)amino>-5-phenyl-1,4,5,6-tetrahydropyrimidine
            (16), was considerably more potent than tricyclic antidepressant (TCA)
            standards.The 2-amino parent compound 27 on the other hand was
            >100-fold as effective as TCA's in in vitro inhibition of norepinephrine
            and dopamine uptake.
 CNR:
            5698810

 Author:
            Jorapur, Vaman S.; Khalil, Zarif H.; Duffley, Richard P.; Razdan, Raj K.;
            Martin, Billy R.; et al.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 28, 6, 1985, 783-787
 Title:
            Hashish: Synthesis and Central Nervous System Activity of Some
            Novel Analogues of Cannabidiol and Oxepin Derivatives of
            D9-Tetrahydrocannabinol
 Abstract:
            Several C-10 substituted cannabidiol (CBD) derivatives and novel
            oxepin derivatives of D9-tetrahydrocannabinol (D9-THC) were
            synthesized and evaluated for biological activity in mice and
            dogs.Treatment of 10-bromocannabidiol diacetate (3) with various
            amines in Me2SO gave the corresponding 10-aminocannabidiol
            derivatives 4-6.Similarly, treatment of 3 with NaN3 gave the azido
            compound 7, which with LiAlH4 afforded the 10-aminocannabidiol
            9.However, reduction of 7 with CrCl2 formed the amide 8, which on
            further reduction with LiAlH4 gave the N-ethyl analogue 10.Coupling of
            9 with 11 in the presence of dicyclohexylcarbodiimide formed 12,
            which then deprotected with HCl to give the analogue 13.The oxepin
            analogue 14a was synthesized from 3 by treatment with Na2CO3 in
            CH3OH/H2O at room temperature.The dimethylheptyl analogue 14b
            was similarly prepared.Incorporation of N-ethyl (10),
            N-methyl-N-propargyl (6), and morpholino (4) groups in CBD at
            position 10 resulted in analogues that were more potent than CBD in
            producing hypoactivity in mice.These analogues had relatively little
            effect on rectal temperature.Selected substitutions at C-10 also
            resulted in analogues that were partially effective in blocking D9-THC
            antinociceptive activity.This blocade was observed particularly in
            compound 10, which also showed unusually toxic
            properties.Incorporation of seven-membered oxepin in the D9-THC
            structure eliminated cannabinoid activity although substitution of the
            pentyl side chain with a 1,2-dimethylheptyl in the oxepin 14b resulted
            in CNS depression in mice.
 CNR:
            5698824

 Author:
            Husain, M. I.; Shukla, Sarveshwar
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 24, 1985, 761-764
 Title:
            Synthesis and Biodynamic Activities of 5-(Substituted
            benzylidene)-3-<p-(N,N-disubstituted
            carbamoyl)phenylaminomethyl>-4-oxothiazolidine-2-thiones
 Abstract:
            Twenty three title compounds (Va-w) have been synthesised by the
            Mannich Reaction between 5-arylidene-4-oxothiazolidine-2-thiones (II)
            and p-(N,N-disubstituted carbamoyl)anilines (IV) and screened for their
            antibacterial activity against B. cereus, S. aureus, M. flavus, S. lutae
            and B. subtilis, antiviral activity against Tobacco Mosaic Virus and
            CNS activities on albino mice.Some of the compounds give interesting
            results.Structure activity relationship has also been studied.
 CNR:
            5703654

 Author:
            Varma, Rajendra S.; Chatterjee, Devesh
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 24, 1985, 1039-1042
 Title:
            Synthesis of Heterocyclic Compounds Incorporating 4-Aminostilbene
 Abstract:
            Different benzazoles undergo Mannich reaction with 4-aminostilbene
            (II), while 5-substituted isatins and N-methylisatins on condensation
            with II give 4-(2-oxo-3-indolinylidenimino)stilbenes (V) and
            4-(1-methyl-2-oxo-3-indolinylidenimino)stilbenes (VI), respectively.V
            are also prepared by amine exchange reaction.Mannich reaction on V
            furnishes 4-(1-aminomethyl-2-oxo-3-indolinylidenimino)stilbenes
            (VII).II on fusion with acetanthranil gives
            4-<2-methyl-4(3H)-oxo-3-quinazolinyl>stilbene (VIII) which undergoes
            condensation with aromatic aldehydes to
            give4-<4(3H)-oxo-2-styryl-3-quinazolinyl>stilbenes (IX).The
            synthesised compounds have been screened for their
            antiinflammatory and CNS activities.
 CNR:
            5703960

 Author:
            Mohan, Rajiv Ravindra; Agarwal, Rajesh; Misra, V. S.
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 24, 1985, 78-82
 Title:
            Synthesis of Some Newer Quinazolinyl-oxadiazoles, Thiosemicarbazides and Thiadiazoles as
            Pharmacologically Active Agents
 Abstract:
            Fifteen new 3-N,N-dialkylaminomethyl-5-(2-alkyl-1,3-quinazolin-4-yloxymethyl)-2-thio-1,3,4-oxadiazoles
            (Va-o) have been synthesised by Mannich reaction on
            5-(2-alkyl-1,3-quinazolin-4-yloxymethyl)-2-thio-1,3,4-oxadiazoles (IVa-c) with different dialkyl
            amines.N1-(2-Alkyl-1,3-quinazolin-4-yloxymethylcarbonyl)-N4-(p-substituted-phenyl)thiosemicarbazides
            (VIa-l) have been prepared by condensing (2-alkyl-1,3-quinazolin-4-oxy)acetic acid hydrazides (III) with
            p-substituted phenyl isothiocyanates.The thiosemicarbazides (VI) undergo cyclisation in AR H2SO4 to
            furnish 4-(2- alkyl-1,3-quinazolin-4-yloxymethyl)-2-(p-substituted phenylamino)-1,3,4-thiadiazoles
            (VIIa-l).Compounds V have been found to be nontoxic and CNS stimulants.Most of them show
            significant protection against carrageenin-induced inflammation.In the anthelmintic activity screening,
            compounds VI show 21.8-57.4percent clearance of N. brasiliensis, whereas compounds VI and VII are
            inactive against H. nana.
 CNR:
            5703971

 Author:
            Sangwan, Naresh K.; Kelkar, Prabhakar M.; Rastogi, Shri Nivas;
            Anand, N.
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 24, 1985, 639-644
 Title:
            Antifertility Agents: Part XLIII - Synthesis of
            3-Aryl-4,5-dihydro-2-substituted-5-tosyl-2H-pyrazolo<4,3-c>quinolines
            and 2,4-Dihydro-3-phenyl<1>benzopyrano<4,3-c>pyrazoles and Their
            Derivatives
 Abstract:
            2,3-Dihydro-1-tosyl-4(1H)-quinolones (5-7) on formylation give the
            corresponding 3-hydroxymethylene derivatives (11-13) of which 12
            and 13 react with piperazine to afford N,N-bis-substituted piperazines
            (15 and 16).Refluxing of 11-13 with substituted hydrazines yields the
            tricyclic
            4,5-dihydro-2-substituted-5-tosyl-2H-pyrazolo<4,3-c>quinolines
            (17-22).Detosylation of 18 gives, besides the expected dihydro
            derivative 23, an aromatised pyrazoloquinoline (24) while the
            detosylation of 19 and 20 affords only the aromatised products 25 and
            26.Condensation of dihydroquinolones (5-7) and chromanones (9, 10)
            with araldehydes produces the corresponding 3-arylidene derivatives
            (27-33).Surprisingly, a similar condensation of
            2,3-dihydro-8-methoxy-1-tosyl-4(1H)-quinolone (8) with araldehydes or
            its formylation results in retroelimination to give N-tosyl-o-anisidine
            (14).Epoxidation of 27-33 gives 3,a-oxido derivatives (34-40) which on
            treatment with NH2-NH2*H2O or PhNHNH2 form the title compounds
            3-aryl-4,5-dihydro-2-substituted-5-tosyl-2H-pyrazolo<4,3-c>quinolines
            (41-46) and 2,4-dihydro-3-phenyl<1>benzopyrano<4,3-c>pyrazoles
            (48, 49).Acetylation of 41 gives 47.Detosylation of 41 affords the
            aromatised pyrazoloquinolines (50) while that of 42 furnished a mixture
            of the dihydro product 52 and the aromatised pyrazoloquinoline
            51.However, detosylation of 42 with pyridine hydrochloride gives only
            51 and no dihydro product.None of the compounds prepared exhibits
            any significant CNS, CVS or antifertility activity except 51 which shows
            weak CNS depressant and hypotensive activities.
 CNR:
            5704002

 Author:
            Kapoor, R. P.; Chhabra, Vinod; Sangita, Km.; Garg, C. P.
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 24, 1985, 539-542
 Title:
            A New Synthesis of 3-(Aryliminomethyl)-4H-1-benzopyran-4-ones and
            3-(Arylaminomethylene)-2,3-dihydro-2-substituted-4H-1-benzopyran-4-ones
            of Potential Biological Activity
 Abstract:
            Five 3-(aryliminomethyl)-4H-1-benzopyran-4-ones (III) and fifteen
            3-(arylaminomethylene)-2,3-dihydro-2-substituted-4H-1-benzopyran-4-ones
            (IV) have been synthesized.The structure of all new compounds have been
            elucidated on the basis of elemental analyses and spectral
            characteristics.Seven compounds have been screened for CNS, CVS,
            antiinflammatory and diuretic activities.
 CNR:
            5704060

 Author:
            Garg, C. P.; Sharma, Vinay Prabha; Kapoor, R. P.
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 24, 1985, 1197-1200
 Title:
            Synthesis of 3-(6-Arylimidazo<2,1-b>-thiazol-3-yl)-2-methylchromones
 Abstract:
            The title compounds (II) have been synthesized by the condensation of
            3-(2-aminothiazol-4-yl)-2-methylchromones(I) with various
            a-bromoacetophenones in abs. ethanol.Their structures have been
            elucidated on the basis of elemental analyses and spectral data (IR,
            PMR, mass).The compound I and II have been screened for their CNS,
            CVS, antiinflammatory and diuretic activities.
 CNR:
            5704130

 Author:
            Kimenis, A. A.; Vitolina, R. O.; Petersone, I. O.; Germane, S. K.; Briede, J. L.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 35, 4, 1985, 672-679
 Title:
            Pharmocological and Toxicological Properties of Ryodipine
 Abstract:
            2,6-Dimethyl-3,5-dimethoxycarbonyl-4-(o-difluoromethoxy-phenyl)-1,4-dihydropyridine
            (ryodipine, PP-1466) causes lasting decrease in systolic and diastolic arterial pressure at
            intravenous and oral administration to aneasthetized animals.In conscious rats with DOCA-salt
            (desoxycortone) and spontaneous hypertension, as well as in rats with hypertension provoked
            by method of cellophane perinephritis, PP-1466 (1 and 10 mg/kg), orally) decreases systolic
            pressure considerably.Therapeutic doses of PP-1466 do not essentially affect rhythm and
            frequency of cardiac contractions.High doses of the drug increase the heart rate.PP-1466
            increases coronary blood flow.PP-1466 antagonizes considerably the pressor effect of
            angiotensin.In this respect PP-1466 is superior to SKF-24260
            (2,6-dimethyl-3,5-diethoxycarbonyl-4-(o-difluoromethoxyphenyl)-1,4-dihydropyridine).PP-1466
            reduces hypotensive reaction and tachycardia induced by isoprenaline administration, inhibits
            decrease in arterial pressure caused by electric stimulation of the vagus nerve and
            administration of acetylcholine.Hypotension caused by PP-1466 and its negative ionotropic
            effect can be antagonized with calcium chloride.In mice and rats PP-1466 at doses exceeding
            10 mg/kg exerts a certain dose-dependent effect on the CNS.More protracted depressant effect
            on the CNS is exerted by nifedipine which was studied parallelly.In rabbits oral PP-1466
            decreases in EEG basic rhythm amplitude both in cortical and subcortical structures.High
            doses of the drug lead to dysrhythmia in bioelectric activity.Acute, subacute and chronic toxicity
            studies in mice, rats and dogs show that PP-1466 possesses low acute toxicity and is well
            tolerated at protracted repeated administration of therapeutic and several times higher doses. -
            Keywords: Antihypertensive agents; Ca2+-antagonists; Nifedipine; PP-1466; Ryodipine,
            pharmacology, Toxicity
 CNR:
            5733963

 Author:
            Baldoli, E.; Bianchi, G.; Corsico, N.; Francesco, G. F. Di
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 35, 5, 1985, 818-826
 Title:
            Pharmacological Studies of
            N-(2,5-Dimethyl-1H-pyrrol-1-yl)-6-(4-morpholinyl)-3-pyridazinamine
            Hydrochloride (MDL-899), a New Long-acting Antihypertensive
            Vasodilator
 Abstract:
            N-(2,5-Dimethyl-1H-pyrrol-1-yl)-6-(4-morpholinyl)-3-pyridazinamine
            hydrochloride (MDL-899) is a new long-acting antihypertensive
            vasodilator which reduces the blood pressure of conscious
            hypertensive rats and dogs to normal levels.The oral doses that reduce
            blood pressure by 50 mmHg are: 4,4 mg/kg in conscious
            spontaneously hypertensive rats (SHR), 18 mg/kg in conscious Milan
            hypertensive strain (MHS) and 1.7 mg/kg in conscious renal
            hypertensive dog (RHD).The i.v. doses are 1.26, 3.2 and 0.9
            mg/kg.The reduction in blood pressure is slow (peak effect at 3 h) and
            long-lasting (more than 7 h) after p.o. or i.v. administration.Tolerance to
            MDL-899 is seen to develop in hypertensive dogs, whereas in
            hypertensive rats this phenomenon never occurs.The compound
            antagonizes the development of hypertension when given to SHR
            between days 25 and 88.The haemodynamic study in conscious
            normotensive rats (labelled microspheres) demonstrated that the fall in
            blood pressure is accompanied by increases in heart rate and cardiac
            output and a decrease in total peripheral resistance.The lack of
            a-blocking activity, in the rat caudal artery "in vitro"; b2-stimulating
            activity, in SHR pretreated with propanolol, and prostaglandin (PG)
            release activity, in SHR pretreated with indometacin, excludes the
            possibility that the hypotension is due to one of these
            mechanisms.MDL-899 given orally to rats has no important depressant
            effects on the CNS at hypotensive or higher doses and induces no
            adrenergic system stimulation symptoms (midriasis, exophthalmus).In
            comparison with hydralazine, it is slower in onset and longer lasting,
            devoid of adrenergic system stimulation, less toxic and
            nonmutagenic.They are equipotent after p.o. treatment. - Key words:
            Antihypertensive agents
            .N-(2,5-Dimethyl-1H-pyrrol-1-yl)-6-(4-morpholinyl)-3-pyridazinamine
            hydrochloride, pharmacology .MDL-899 .Vasodilators
 CNR:
            5734331

 Author:
            Jacob, James N.; Shashoua, Victor E.; Campbell, Alexander;
            Baldessarini, Ross J.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 28, 1, 1985, 106-110
 Title:
            g-Aminobutyric Acid Esters. 2. Synthesis, Brain Uptake and
            Pharmacological Properties of Lipid Esters of g-Aminobutyric Acid
 Abstract:
            Two lipid esters of U-14C-labeled and unlabeled g-aminobutyric acid
            (GABA) were synthesized to test the possibility that natural lipid
            analogues, which resemble normal components of lipid bilayer
            membranes, can penetrate the blood-brain barrier and transport
            exogenous GABA to the brain.The uptake of
            1-linolenoyl-2,3-bis(4-aminobutyryl)propane-1,2,3-triol and
            1,2-dilinolenoyl-3-(4-aminobutyryl)propane-1,2,3-triol into mouse brain
            relative to liver was found to be, respectively, 75- and 127-fold greater
            than that of free GABA.The results indicate that there is littleor no
            blood-brain barrier for the GABA ester molecules at doses up to 0.36
            mmol/kg.Both ester compounds, but neither free GABA nor the lipid
            components delivered systemically, demonstrated central nervous
            system depressant properties by inhibiting the general motor activity of
            mice.Brain tissue has esterase activity which can release GABA from
            these compounds.This suggests that these compounds function as
            "prodrugs" to release GABA in the CNS.
 CNR:
            5745130

 Author:
            Varma, Rajendra S.; Chauhan, Sudha; Prasad, C. R.
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 24, 1985, 280-285
 Title:
            Synthesis of Substituted 2-Phenylbenzoxazoles as CNS Active Agents
 Abstract:
            The reaction of <p-(2-benzoxazolyl)phenoxyacetyl>hydrazine (III) with
            CS2 and ethanolic KOH furnishes
            2-<2'-(benzoxazolyl)phenoxymethyl>-5-mercaptooxadiazole (IV) which
            on Mannich reaction with piperidine and morpholine gives the bases
            Va and Vb respectively.Condensation of isatin and 5-chloroisatin with
            III affords VI and VII which on Mannich reaction furnish the bases VIII
            and IX respectively.Condensation of N-methylisatin and
            N-methyl-5-chloroisatin with III gives X and XI.Treatment of
            2-(p-hydroxyphenyl)benzoxazole (I) with allyl bromide furnishes the
            allyl derivative (XII) while acetylation of it with Ac2O gives XIII.Mannich
            reaction of benzothiazolin-2-thione, benzoxazolin-2-one and
            6-nitrobenzoxazolin-2-one with 2-(p-aminophenyl)benzoxazole (XIV)
            affords the compounds XV, XVIa and XVIb, respectively.Treatment of
            acetanthranil (XVII) with XIV gives
            3-<p-(2-benzoxazolyl)phenyl>-2-methyl-4-quinazolone
            (XVIII).Condensation of isatin and N-methylisatin with XIV furnishes
            XIX and XX respectively.The former (XIX) on Mannich reaction with
            morpholine and formaldehyde gives rise to XXI.
 CNR:
            5749972

 Author:
            Ossman, Abdel Rahman El Nasser; Safwat, H. M.; Aziza, Mohsen A.
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 24, 1985, 333-335
 Title:
            Synthesis and Pharmacological Activity of Some New
            4(3H)-Quinazolone Derivatives
 Abstract:
            New derivatives of 2-methyl-4(3H)-quinazolone have been prepared
            and their structures assigned on the basis of IR, PMR and mass
            spectra.Some of them show CNS depressant activity.
 CNR:
            5750007

 Author:
            Lakhan, Ram; Singh, Om Prakash
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), EN, 318, 3, 1985,
            228-238
 Title:
            Syntheses of Some New 4(3H)-Quinazolinones as Potential CNS
            Active Agents
 Abstract:
            More than fifty 2-(N-substituted
            aminoethylthio)-3-aryl-6-iodo-4(3H)-quinazolinones 2-6 have been
            prepared.Some of them were tested for CNS activities on mice and
            found to be either depressants or stimulants.
 CNR:
            5776268

 Author:
            Bickel, M.; Alpermann, H.-G.; Roche, M.; Schemann, M.; Ehrlein, H.-J.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 35, 9, 1985, 1417-1426
 Title:
            Pharmacology of a Gut Motility Stimulating Enkephalin Analogue
 Abstract:
            The enkephalin analogue pentapeptide Hoe 825
            (Tyr-D-Lys-Gly-Phe-L-homocysteine-thiolactone) is a mixed m/d opiate
            agonist.The peptide stimulated interdigestive gut motility at all parts of
            the intestine in conscious and anaesthetized animals.In dogs digestive
            motility, measuring mechanical activity, was stimulated with respect to
            segmental and propulsive properties.The canine uterus was sensitive
            to the enkephalin.Hoe 825 acts by i.v. or s.c. application, whereas the
            latter increases the duration of action significantly.The compound's
            effect can be blocked by naloxone indicating a receptor mediated
            action, which is localised peripherally.The compound is devoid of a
            dependence risk, because it does not penetrate into the CNS.At
            therapeutic doses (in the dog 0.5-2 mg/kg i.v.) the compound does not
            affect cardiovascular, renal or endocrine functions and was without
            effect on serum blood glucose levels in rats and rabbits. - Key words:
            Enkephalin analogue pentapeptide, pharmacology; Enkephalins; Hoe
            825; Intestinal motility, stimulation; Opiate receptors
 CNR:
            5792824

 Author:
            Wagner, Hildebert; Fischer, Manfred; Lotter, Hermann
 Reference:
            Journal, ZNBAD2, Z.Naturforsch.B Anorg.Chem.Org.Chem., EN, 40, 9,
            1985, 1226-1228
 Title:
            New Bufadienolides from Kalanchoe daigremontiana Hamet et Perr.
            (Crassulaceae)
 Abstract:
            Five biosynthetically related bufadienolides were isolated from
            Kalanchoe daigremontiana Hamet et Perr. and structurally elucidated
            by X-Ray and NMR techniques.Two compounds were orthoacetates
            which showed strong CNS activity. - Key words: Kalanchoe
            daigremontiana, Bufadienolides, X-Ray, Daigremontianin,
            Daigredorigenin, Bersaldegenin Derivatives
 CNR:
            5794393

 Author:
            MacDiarmid, Joan E.; Rose, William C.; Biddle, William C.; Perlman,
            Michael E.; Breiner, Robert G.; et al.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 28, 11, 1985, 1685-1691
 Title:
            Synthesis and Properties of Bis(2,2-dimethylaziridinyl)phosphinic
            Amides: A Series of New Antineoplastic Agents
 Abstract:
            In continuation of efforts to improve the antitumor selectivity of the
            2,2-dimethylaziridine class of alkylating agents, a series of
            N-substituted bis(2,2-dimethyl-1-aziridinyl)phosphonic amides has
            been synthesized and evaluated.All of these compounds (3-15) were
            tested in vivo against leukemia P-388 in mice, where most of them
            caused significant increase of survival time at nontoxic dose
            levels.Some of the most active compounds were also tested against
            leukemia L1210, B16 melanoma, and colon 26 carcinoma; in the latter
            tests, the parent unsubstituted amide 3 appeared to show the highest
            antitumor activity.Since the dose-limiting toxicity of the clinically tested
            prototypes of this class of anticancer agents AB-132 (1) and AB-163 (2)
            had been found to be CNS toxicity attributable mainly to the inhibition
            of cholinesterase, the compounds were tested in vitro against the
            cholinesterases from horse serum, electric eel, and bovine
            erythrocytes, as well as in vivo for the inhibition of the cholinesterases
            present in the whole blood of mice.In all of these assays, the various
            members of the present series showed a wide range of
            anticholinesterase activities, ranging from almost zero (for 3) to even
            higher potency than that of the prototype 2.A similarly range of stability
            was observed toward hydrolytic ring opening of the
            2,2-dimethylaziridine moieties.Several of the compounds, particularly
            3, deserve further study.
 CNR:
            5805574

 Author:
            Ghosal, Shibnath; Jaiswal, Dinesh K.; Singh, Sushil K.; Srivastava,
            Radhey S.
 Reference:
            Journal, PYTCAS, Phytochemistry, EN, 24, 4, 1985, 831-834
 Title:
            DICHOTOSIN AND DICHOTOSININ, TWO ADAPTOGENIC
            GLUCOSYLOXY FLAVANS FROM HOPPEA DICHOTOMA
 Abstract:
            Hoppea dichotoma; Gentianaceae; roots; glucosyloxy flavans;
            dichotosin, (2S)-7,4'-dimethoxy-5-O-b-D-glucupyranosylflavan;
            dichotosinin; 7,3',4'-trimethoxy-5-O-b-D-glucopyranosylflavan; diffutin;
            7-hydroxy-3',4'-dimethoxy-5-O-b-D-glucopyranosylflavan; central
            nervous sytem (CNS) active agents; adaptogens.From the roots of
            Hoppea dichotoma, collected before flowering, two new naturally
            occuring glucosyloxyflavans, dichotosin and dichotosinin, have been
            isolated and characterized by means of comprehensive spectral
            analyses, chemical transformation and synthesis of the aglucone of
            dichotosin.This is the first report of dichotosinin from a natural
            source.Additionally, one known glucosyloxyflavan, diffutin, earlier
            reported in another Gentianaceae species (Canscora diffusa) also has
            now been isolated from this species.The glucosyloxyflavans,
            individually and in combination, produced varying degrees of
            adaptogenic (anti-stress-anti-anxiety) activity in animal models.This
            observation is consistent with the use of the plant extract as a nerve
            tonic in Ayurvedic medicine.
 CNR:
            5830164

 Author:
            Venugopalan, Changaram S.; Jenkins, Howard J.
 Reference:
            Journal, JPMSAE, J.Pharm.Sci., EN, 74, 6, 1985, 681-684
 Title:
            Cardiovascular Effects of Two Potential b-Hydroxylase Inhibitors
 Abstract:
            The purpose of this study was to evaluate the cardiovascular effects of
            two potential b-hydroxylase inhibitors, a dithiocarbamate and a
            thiourea derivative of d-amphetamine, 1 and 2, respectively.These
            compounds when given intravenously elicited a significant
            dose-dependent depressor effect in normotensive rats and dogs
            anesthetized with chloralose-urethane.The hypotensive effect of these
            compounds appears to be the result of a combination of two action
            components: (a) the major component, which can be blocked by
            atropine, exerted through the parasympathetic division and (b) a
            decreased availability of sympathetic neurotransmitter at the synaptic
            cleft.A CNS-stimulant effect of these compounds is suggested by their
            ability to reduce hexobarbital sleeping time in mice and their analeptic
            effect in all anesthetized animals employed.
 CNR:
            5836436

 Author:
            Kulkarni, Y. D.; Abdi, S. H. R.; Sharma, V. L.; Dua, P. R.; Shanker, G.
 Reference:
            Journal, JICSAH, J.Indian Chem.Soc., EN, 62, 3, 1985, 231-233
 Title:
            Synthesis of 2-Substituted-phenyl-3-aroyl-4-oxo-4H-1,S.231-233zines
            as Possible Antifertility/CNS Active Agents
 Abstract:
            Twelve new 2-substituted phenyl-3-aroyl-4-oxo-4H-1,3-benzoxazines
            have been synthesised and screened for their toxicity, antifertility and
            CNS activities.These compounds exhibited antifertility activity upto
            50percent at the dose levels studied and were found to possess mild
            CNS effects as well.
 CNR:
            5863984

 Author:
            Chaurasia, M. R.; Sharma, Ajay K.
 Reference:
            Journal, JICSAH, J.Indian Chem.Soc., EN, 62, 4, 1985, 308-309
 Title:
            Synthesis of Some New 4(3H)Quinazolinones as CNS Depressants and
            Antifungal Agents
 Abstract:
            Several new
            6,8-dichloro-2-phenyl-3<(substituted)benzothiazol-2'-yl>-4(3H)quinazolinones
            have been synthesised and screened for their CNS depressant activity.Their
            fungicidal activity has also been screened on Aspergillus niger and Alternaria
            alternata at two dilutions.The antifungal screening of compounds reveals that
            some of them inhibit fungal growth.
 CNR:
            5864535

 Author:
            Grandolini, G.; Rossi, C.; Tiralti, M. C.; Orzalesi, G.; Regis, M. de
 Reference:
            Journal, FRPSAX, Farmaco Ed.Sci., EN, 40, 4, 1985, 221-236
 Title:
            STUDIES ON ANNELATED 1,4-BENZOTHIAZINES AND
            1,5-BENZOTHIAZEPINES. I. Synthesis of
            4H-s-triazolo<3,4-c>-1,4-benzothiazine and derivatives with potential
            CNS activity
 Abstract:
            As a part of a program toward the synthesis and the pharmacological
            studies on annelated 1,4-benzothiazines and 1,5-benzothiazepines, a
            number of 4-H-s-triazolo<3,4-c>-1,4-benzothiazine derivatives were
            prepared and tested for their CNS activity. - The syntheses of the new
            tricyclic compounds (VII) were performed via the
            2H-1,4-benzothiazine-3(4H)-thiones (II) which were obtained by
            Lawesson's thiation of lactams (I).Compounds (II) and their
            S-methyl-thioethers (III), quantitatively obtained by PTC method, were
            reacted with acylhydrazines to give the title compounds.Some
            triazolobenzothiazines (VII) were also prepared from
            3-hydrazinoderivatives (IV) by cyclization with either an aliphatic acid
            or the corresponding orthoester.
 CNR:
            5876882

 Author:
            Bartl, Vaclav; Kmonicek, Vojtech; Sedivy, Zdenek; Svatek, Emil;
            Protiva, Jiri; Protiva, Miroslav
 Reference:
            Journal, CCCCAK, Collect.Czech.Chem.Commun., EN, 49, 10, 1984,
            2295-2308
 Title:
            THIOXANTHENE DERIVATIVES OF PHARMACOLOGICAL
            INTEREST: 1,2,4-TRICHLORO AND 2,4,5,6-TETRACHLORO
            DERIVATIVES OF
            9-(3-DIMETHYLAMINOPROPYLIDENE)THIOXANTHENE
 Abstract:
            Reactions of 2,4,5-trichlorothiophenol (II) with 2-iodobenzoic acid and
            2,3-dichlorothiophenol with 3,5-dichloro-2-iodobenzoic acid gave the
            acids III and IX which were cyclized to thioxanthones VI and
            XV.Reactions of these ketones with
            3-dimethylaminopropylmagnesium chloride afforded the amino
            alcohols VII and XVI which were transformed by the acid catalyzed
            dehydration to the title compounds I and VIII.
            2-Chloro-9-<1-(2-hydroxyethyl)-4-piperidylidene>thioxanthene (XVII)
            was obtained by a modified synthesis.Compound I is inactive in the
            line of the CNS effects but ithas high inhibitory activity in the in vitro
            tests towards gram-positive microorganisms.Compound XVII has
            properties of a mild tranquillizer.
 CNR:
            5559707

 Author:
            Bartl, Vaclav; Svatek, Emil; Dlabac, Antonin; Wildt, Stanislav; Protiva, Miroslav
 Reference:
            Journal, CCCCAK, Collect.Czech.Chem.Commun., EN, 49, 8, 1984, 1816-1826
 Title:
            11-(3-<4-(2-HYDROXYETHYL)PIPERAZINO>PROPYLIDENE)-6,11-DIHYDRODIBENZO<b,e>THIEPIN,
            ITS 2-CHLORO DERIVATIVE AND SOME RELATED COMPOUNDS AS POTENTIAL ANTIPSYCHOTIC
            AGENTS; SYNTHESIS AND PHARMACOLOGY
 Abstract:
            Substitution reactions of (E)-11-(3-bromopropylidene)-6,11-dihydrodibenzo<b,e,>thiepin (VIIIa) and its
            2-chloro derivative VIIIb with 1-(2-hydroxyethyl)piperazine gave the title compounds IIIa and IIIb which
            afforded by treatment with acetic anhydride, decanoyl chloride and 3,4,5-trimethoxybenzoyl chloride the
            esters IVab-VIab.Reduction of the olefinic compounds IIIa and IIIb with hydroiodic acid resulted in the
            saturated amines IXa and IXb.The piperazine derivative X was obtained by a substitution reaction of
            2,11-dichloro-6,11-dihydrodibenzo<b,e>thiepin with1-(2-hydroxyethyl)piperazine.The amino alcohols IIIa
            and IIIb, as well as their acetates and 3,4,5-trimethoxybenzoates, are almost devoid of the CNS
            effects.The decanoates Va and Vb have not the properties of the depot antipsychotics (neither
            antidepressants, nor neuroleptics).The saturated amino alcohol IXa showed some antihistamine,
            spasmolytic and adrenolytic effects.
 CNR:
            5560225

 Author:
            Escale, Roger; Khayat, Ammar El; Vidal, Jean-Pierre; Girard,
            Jean-Pierre; Rossi, Jean-Claude
 Reference:
            Journal, JHTCAD, J.Heterocycl.Chem., FR, 21, 1984, 1033-1040
 Title:
            Analogues du nor-B benzomorphane. I. Synthese des methano-3,5
            tetrahydro-2,3,4,5 1H-benzazepines et derives
 Abstract:
            A series of new homologous B-norbenzomorphans, the
            3,5-methano-2,3,4,5-tetrahydro-1H-1- and 2-benzazepines including 7-
            and 8-nitro or amino derivatives have been synthesized as potential
            CNS drugs.
 CNR:
            5562335

 Author:
            El-Kerdawy, Mohamed M.; Ismaiel, Abdel Kader M.
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 23, 9, 1984, 844-848
 Title:
            Synthesis and Biological Activity of Some Isomeric Benzotriazoles
 Abstract:
            A number of isomeric benzotriazoles (1-42) have been synthesised
            and their structures established on the basis of elemental analyses, IR,
            UV and mass spectral data.Separation of isomeric products from their
            mixtures has been discussed.Four compounds (7, 10, 13, and 23)
            have been screened for their toxicity and psychotogenic
            activity.Compounds 7 and 23 cause CNS depression whereas 10 and
            13 produce CNS stimulation for a short duration (3-5 min.).These
            compounds,however, are toxic.
 CNR:
            5574154

 Author:
            Joshi, Krishna C.; Chand, Pooran; Dandia, Anshu
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 23, 8, 1984, 743-745
 Title:
            Studies in Spiroheterocycles: Part II - Reactions of Fluorine Containing
            Indole-2,3-diones with 1,2-Phenylenediamines and 2,3-Diaminopyridine
            in Different Media
 Abstract:
            Reactions of fluorine containing indole-2,3-diones (III, IV) with fluorinated
            1,2-phenylenediamines (I) and 2,3-diaminopyridine (II) in different media
            have been investigated.In gl. acetic acid, indole-2,3-diones (III) afford
            exclusively indolo<2,3-b>quinoxazolines (V) with I but in ethanol, a
            mixture of products is obtained.On the other hand,
            1,3-dihydrospiro<2H-benzimidazole-2,3'-<3H>indol>-2'(1'H)-ones (VI) are
            the main products formed by I and 1-acetylindole-2,3-diones (IV) in both
            the media. 2,3-Diaminopyridine (II) produces
            1,3-dihydrospiro<2H-imidazo<4,5-b>pyridine-2,3'<3H>indol>-2'(1'H)-ones
            (VII, VIII) with both III and IV in ethanol as well as in gl. acetic acid, but the
            yields of the products are solvent dependent.The proposed structures of
            the products have been fully corroborated by their elemental analysis, IR,
            PMR, 19F NMR and mass spectral data.Preliminary screening shows the
            spiro compounds to be potent CNS depressants and nontoxic.
 CNR:
            5574236

 Author:
            Shridhar, D. R.; Jogibhukta, M.; Vishwakarma, L. C.; Joshi, P. P.;
            Narayan, G. K. A. S. S.; et al.
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 23, 5, 1984, 445-448
 Title:
            Synthesis & Biological Activity of Some Substituted
            4H-<1,2,4>Triazolo<3,4-c><1,4>benzoxazines /SUB>
            4H-<1,2,4>Triazolo<3,4-c><1,4>benzothiazines
 Abstract:
            A number of derivatives of 4H-<1,2,4>triazolo<3,4-c><1,4>benzoxazine
            and 4H-<1,2,4>triazolo<3,4-c><1,4>benzothiazine have been
            synthesised and screened for their antiinflammatory, CNS and CVS
            activities.Representative compounds have also been evaluated for
            their antimicrobial and anthelmintic activities.Several compounds in
            this series are found to possess significant antiinflammatory activity
            against carrageenin-induced rat paw oedema, compound 11 being the
            most active member of this series showing 44.35 percent inhibition at
            200 mg/kg (p. o.) dose.In addition, compound 8 shows promising CNS
            depressant activity while a few others exhibit moderate antifungal and
            antitubercular activities.
 CNR:
            5574515

 Author:
            Deshmukh, A. A.; Mody, M. K.; Ramalingam, T.; Sattur, P. B.
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 23, 8, 1984, 793-795
 Title:
            Synthesis and Pharmacology of
            2-Aryl/aralkyl-5-aryl/aralkyl/diaralkyl-s-triazolo<3,4-b>-1,3,4-thiadiazoles
 Abstract:
            A series of s-triazolo<3,4-b>-1,3,4-thiadiazoles (III) carrying aryl or
            aralkyl group at 2-position and aryl, aralkyl or diaralkyl group at
            5-position have been synthesised and evaluated for their biological
            activities.Some of the compounds exhibit strong CNS depressant and
            mild to moderate antiinflammatory action in experimental animals.
 CNR:
            5575351

 Author:
            Kapoor, R. P.; Rastogi, M. K.; Garg, C. P.
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 23, 3, 1984, 285-286
 Title:
            Synthesis of 3-N-Substituted Aminoflavones as Potential CNS Agents
 Abstract:
            3-N-Substituted aminoflavones (VI) have been synthesized by the
            action of appropriate secondary amines on 3-bromoflavone (III).In the
            preparation of III by a known procedure involving the bromination of
            flavone (II), a mixture of three products has been obtained rather than
            one product as reported by Pendse <Chem Abstr, 51 (1957)
            5062>.The structures of VI and two of the bromination products have
            been established on the basis of their elemental analyses and spectral
            data.Compounds VI exhibit weak CNS depressant, hypotensive and
            hyperthermic activities.
 CNR:
            5575679

 Author:
            Shridhar, D. R.; Sastry, C. V. Reddy; Chaturvedi, S. C.; Gurumurthy, R.;
            Singh, P. P.; et al.
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 23, 7, 1984, 692-694
 Title:
            Synthesis and Pharmacology of Some New Oxime Ethers Derived
            from 2-Acetyl-5-arylthiophenes
 Abstract:
            Several new 5-arylthiophene-2-acetoxime ethers (1-28) have been
            synthesised and screened for their pharmacological activities.Some of
            these compounds possess moderate antiinflammatory and mild CNS
            depressant activities.The intermediate
            2-acetyl-5-(p-ethyl/p-iso-propyl/3,4-dimethylphenyl)thiophenes (1b-d)
            and their oximes (IIb-d) have been reported for the first time.
 CNR:
            5576106

 Author:
            Kapoor, R.P.; Rastogi, M.K.; Khanna, Rekha; Garg, C.P.
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 23, 4, 1984, 390-392
 Title:
            Synthesis of Thiazolylchromones as Potential CNS Agents
 Abstract:
            A number of new thiazolylchromones (Va-m) have been prepared and
            their structures asssigned on the basis of elemental analyses and
            spectral data.Some of them exhibit weak CNS depressant,
            hypotensive and hyperthermic activities in gross observation test.
 CNR:
            5577038

 Author:
            Chmielewska, Barbara
 Reference:
            Journal, PHARAT, Pharmazie, EN, 39, 4, 1984, 259-262
 Title:
            Pharmacological Properties of New Cyclic Derivatives of
            Phenylsuccinimide and Their Influence of Noradrenaline, Dopamine,
            Serotonin, 5-Hydroxyindoleacetic Acid, Gamma-Aminobutyric Acid
            Concentrations and Monoaminooxidase Activity in Animal Brains
 Abstract:
            Three new cyclic derivatives of phenylsuccinimide (1-10, 1-11 and
            IL-7) were subjected to preliminary pharmacological studies in
            animals.Minimal peripheral action and inhibitory influence on the CNS
            were noted (only IL-7 was found to stimulate CNS).Neurotoxic effects
            were similar to those of the classical succinimides.Anticonvulsant
            activity and behavioral effects of tested compounds are discussed in
            the light of their influence on neurotransmitters.
 CNR:
            5685756

 Author:
            Joshi, K. C.; Patni, R.; Chand, P.; Sharma, V.; Bhattacharya, S. K.;
            Rao, Y. V.
 Reference:
            Journal, PHARAT, Pharmazie, EN, 39, 3, 1984, 153-155
 Title:
            Synthesis and Central Nervous System Activities of Certain
            Fluorine-Containing 3-Substituted Indol-2-ones
 Abstract:
            Several fluorine-containing 3-aroylmethyl-3-hydroxyindol-2-ones
            (4a-g), 3-aroylmethyleneindol-2-ones (5a-g) and
            3-aroylmethylindol-2-ones (6a-g) were synthesized from the
            corresponding fluorine-containing indole-2,3-diones and appropriate
            ketones.The compounds were characterized by spectral
            studies.Representative compounds of each series were tested on mice
            for CNS activities, viz. analgesic and anticonvulsant and the effects
            were also observed against amphetamine-induced stereotypy, on
            conditioned avoidance response and on potentiation of pentobarbitone
            sodium hypnosis.Of the compounds examined, the greatest degree of
            activity was observed in 3-aroyl-methyleneindol-2-ones with a
            pronounced unsaturation in the system.
 CNR:
            5689500

 Author:
            Szirtes, Tamas; Kisfaludy, Lajos; Palosi, Eva; Szporny, Laszlo
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 27, 6, 1984, 741-745
 Title:
            Synthesis of Thyrotropin-Releasing Hormone Analogues. 1. Complete
            Dissociation of Central Nervous Effects from Thyrotropin-Releasing
            Activity
 Abstract:
            Twenty-four thyrotropin-releasing hormone (TRH) analogues
            containing mainly aliphatic amino acids in position 2 were synthesized
            and tested for central nervous system (CNS) and hormonal (TSH)
            activity.Application of the pentafluorophenyl ester method in the
            syntheses resulted in optimal yields and high purity of the
            products.The neutral tripeptides pGlu-Nva-Pro-NH2 (9),
            pGlu-Nle-Pro-NH2 (10), and pGlu-Leu-Pro-NH2 (3) with a three- or
            four-membered straight or branched alkyl side chain in the position of
            the central amino acid had 2.5 to 10 times stronger anticataleptic effect
            than TRH, demonstrating that the presence of histidine is not essential
            for the CNS activity.Analogue 9 exhibited tenfold anticataleptic activity
            as compared to TRH, and it was found to be fully inactive in the
            release of TSH.
 CNR:
            5699037

 Author:
            Rajagopalan, P.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 27, 8, 1984, 946-947
 Title:
            Synthetic CNS Agents. 1.
            (+/-)-1,2,3,4,4a,5,10,10a-Octahydro-5,10<1',2'>benzenobenz<g>isoquinoline
            Hydrochloride. A New, Highly Potent, Potential Antidepressant
 Abstract:
 CNR:
            5699208

 Author:
            Meyer, Walter E.; Tomcufcik, Andrew S.; Chan, Peter S.; Emma, John E.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 27, 12, 1984, 1705-1710
 Title:
            N2-(4-Substituted-2,6-dichlorophenyl)-N1,N1-dimethylformamidines as
            Antihypertensive and Diuretic Agents
 Abstract:
            The synthesis of a series of
            N2-<4-<(arylmethyl)amino>-2,6-dichlorophenyl>-N1,N1-dimethylformamidines
            that caused marked blood pressure lowering and/or diuresis in spontaneously
            hypertensive rats (SHR) is reported.Diuretic activity was not always associated
            with acute antihypertensive activity.Central nervous system effects, most
            notably sedation, were observed.Compound 9d, which lowered arterial blood
            pressure 37 mmHg in SHR when dosed at 100 mg/kg, was further evaluated
            in chronic hypertensive dogs because of apparent minimal CNS effects.A
            reduction in arterial blood pressure of 32 mmHg at 1.0 mg/kg during a 6-h
            postdosing interval was observed.This response was unrelated to a- or
            b-adrenergic blockade, angiotensin I antagonism, or neuronal or ganglionic
            blockade.CNS effects were also observed.
 CNR:
            5744463

 Author:
            Weinhardt, Klaus; Beard, Colin C.; Dvorak, Charles; Marx, Michael;
            Patterson, John; et al.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 27, 5, 1984, 616-627
 Title:
            Synthesis and Central Nervous System Properties of
            2-<(Alkoxycarbonyl)amino>-4(5)-phenyl-2-imidazolines
 Abstract:
            A series of 2-<(alkoxycarbonyl)amino>-4(5)-phenyl-2-imidazolines was
            prepared and evaluated for central nervous system (CNS) effects
            (antidepressant, anticonvulsant, muscle relaxant, and depressant) in
            animal models.Some separation of those CNS activities was achieved
            through substitutions on the phenyl and imidazoline
            moieties.Halo-substituted phenyl compounds were among the most
            potent antidepressants in this series, while imidazole N-alkylation
            produced compounds with increased depressant effects (loss of
            righting reflex, mouse behavior).Comparison of in vitro and in vivo data
            for pairs of 2-<(methoxycarbonyl)amino>-4(5)-phenyl-2-imidazolines
            and their parent, 2-amino-4(5)-phenyl-2-imidazolines, suggests that the
            title compounds were prodrugs for the
            2-amino-4(5)-phenyl-2-imidazolines in inhibition of norepinephrine
            reuptake.
 CNR:
            5745619

 Author:
            Shahsoua, Victor E.; Jacob, James N.; Ridge, Richard; Campbell,
            Alexander; Baldessarini, Ross J.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 27, 5, 1984, 659-664
 Title:
            g-Aminobutyric Acid Esters. 1. Synthesis, Brain Uptake, and
            Pharmacological Studies of Aliphatic and Steroid Esters of
            g-Aminobutyric Acid
 Abstract:
            Labeled and unlabeled aliphatic and steroid esters of
            g-amino<U-(14)C>butyric acid (GABA) were synthesized and tested for
            their capacity to penetrate the blood-brain barrier and for evidence of
            central neuropharmacological activity in rodents.The uptake of the
            labeled 9,12,15-octadecatrienyl (linolenyl), 3-cholesteryl, 1-butyl, and
            the
            9-fluoro-11b-17-dihydroxy-16a-methyl-3,20-dioxopregna-1,4-dien-21-yl
            (dexamethasone) esters of GABA into mouse brain increased 2-, 25-,
            74-, and 81-fold over GABA, respectively.The cholesteryl ester of GABA
            depressed the general motor activity of mice and rats in a
            dose-dependent manner, whereas the 1-butyl, linolenyl, and
            dexamethasone esters were inactive by this test.Studies of the rates of
            hydrolysis, GABA receptor binding capacity, and octanol/water partition
            coefficients indicated that pharmacological activity of the esters after
            entry into the central nervous system (CNS) was dependent on their
            capacity to release GABA by enzymatic hydrolysis and their lipid
            solubility.
 CNR:
            5746156

 Author:
            Butler, Donald E.; Nordin, Ivan C.; L'Italien, Yvon J.; Zweisler, Lynette;
            Poschel, Paul H.; Marriott, John G.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 27, 5, 1984, 684-691
 Title:
            Amnesia-Reversal Activity of a Series of
            N-<(Disubstituted-amino)alkyl>-2-oxo-1-pyrrolidineacetamides, Including
            Pramiracetam
 Abstract:
            A series of N-<(dialkylamino)alkyl>-2-oxo-1-pyrrolidineacetamides was
            synthesized.The title compounds reversed electroconvulsive shock (ECS)
            induced amnesia in mice when administered subsequent to the ECS
            treatment and were inactive in a general observational test for central
            nervous system (CNS) activity.Active compounds exhibited an inverted
            U-shaped dose-response curve.Among the compounds with the broadest
            dose-response curve, as well as the most potent, were those with the
            N-<2-<bis(1-methylethyl)amino>ethyl> or 2,6-dimethylpiperidinoethyl
            residues as amide substituent.The N-(dialkylamino) substituent markedly
            enhances amnesia-reversal activity, with ethylene providing the optimal
            chain
            length.N-<2-<Bis(1-methylethyl)amino>ethyl>-2-oxo-1-pyrrolidineacetamide
            N-(dialkylamino) substituent was selected for preclinical toxicological
            evaluation, assigned the investigational number CI-879 and the U.S.
            adopted name (USAN) pramiracetam.Pramiracetam demonstrated a wide
            margin of safety in animals and was well tolerated in normal human
            volunteers.Is has shown encouraging activity in an open label trial in patients
            with primary degenerative dementia (PDD or senile dementia of the
            Alzheimer's type).
 CNR:
            5746161

 Author:
            Farquhar, David; Benvenuto, John
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 27, 12, 1984, 1723-1727
 Title:
            1-Aryl-3,3-dimethyltriazenes: Potential Central Nervous System Active
            Analogues of 5-(3,3-Dimethyl-1-triazeno)imidazole-4-carboxamide
            (DTIC)
 Abstract:
            A series of 19 aryldimethyltriazenes were synthesized as potential
            central nervous system (CNS) active analogues of
            5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC).The
            compounds were screened in mice against both intraperitoneally (ip)
            and intracerebrally (ic) implanted L1210 leukemia.Select compounds
            were further screened against ic implanted ependymeblastoma, and
            one compound was additionally screened against ic implanted B16
            melanoma.Although several compounds were as effective as DTIC at
            prolonging the life span of mice bearing ip implanted L1210 leukemia,
            only 4-(3,3-dimethyl-1-triazeno)benzamide (DTB) and
            4-(3,3-dimethyl)1-triazeno)benzoic acid (DTBA) were significantly
            active against the ic implanted tumor.DTB, unlike DTIC, was equally
            effective against both the ip and the ic implanted tumor, clearly
            indicating that it penetrated into the CNS in therapeutic
            concentration.DTB was also active against ic implanted
            ependymoblastoma and ic implanted B16
            melanoma.Aryldimethyltriazenes, particularly DTB, may have a role in
            the treatment of tumors metastatic to the CNS.They may also be
            effective against primary brain tumors.
 CNR:
            5746345

 Author:
            Knabe, Joachim; Buech, Horst P.; Reischig, Dirk
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), EN, 317, 7, 1984,
            614-619
 Title:
            Piperidinediones, III: Structure-Activity Relationships of the
            Enantiomers of a Series of 2,6-Piperidinedione Derivatives
 Abstract:
            Among the racemic 2,6-piperidinediones 1-6, compound 6 has the
            highest anesthetic activity.The enantiomers of 1, 2, 4 and 5 possess
            different anesthetic potencies depending on the nature of the aliphatic
            side chain.The S(-)-enantiomers of the piperidinediones 2, 3 and 5
            cause initial CNS stimulation with convulsive symptoms followed by
            anesthesia.
 CNR:
            5749525

 Author:
            Frohberg, Harald
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 34, 9b, 1984, 1137-1144
 Title:
            Results of Toxicological Studies on Praziquantel
 Abstract:
            Praziquantel
            (2-cyclohexylcarbonyl-1,2,3,6,7,11b-hexahydro-4H-pyrazino<2,1-a>isoquinolin-4-one,
            EMBAY 8440, Biltricide) is an anthelminthic drug with activity against all species of
            schistosomes pathogenic to man and a wide range of cestodes, including the
            cisticerci of Taenia solium in human tissues and organs, also the CNS.Praziquantel
            does not reveal any undesired pharmacodynamic effects.After oral administration
            praziquantel is quantitatively and rapidly absorbed, metabolized and excreted as a
            variety of metabolites predominantly via the kidneys.The acute toxicity in rats, mice,
            rabbits and dogs is very low.Rats tolerated by oral administration doses of up to 1000
            mg/kg repeated daily for four weeks, and dogs up to 180 mg/kg for 13 weeks without
            any organ damage.Praziquantel did not disturb reproduction in rats (up to
            F2-generation), nor did it reveal teratogenic effects in mice, rats and rabbits.In
            extensive mutagenicity trials performed by different laboratories worldwide, in a variety
            of test systems, no induction of point mutations, gene conversion, DNA-repair, sister
            chromatid exchanges (SCEs), or X-linked recessive lethals was detected.Besides,
            Salmonella tests with urines of Praziquantel treated mice, rats, healthy and
            Schistosoma-infected persons gave no indication of a mutagenic effect.In different in
            vivo mammalian assays praziquantel not mutagenic either.Low toxicity of praziquantel
            was demonstrated also in the combined chronic toxicity and carcinogenicity tests
            which were performed in rats and Syrian hamsters.In none of these species
            praziquantel exerted a carcinogenic action, and both doses were tolerated. - Key
            words: Biltricide; EMBAY 8440; Praziquantel, results of toxicological studies
 CNR:
            5795386

 Author:
            Dhasmana, A.; Mehrotra, S.; Gupta, T. K.; Bhargava, K. P.; Parmar, S.
            S.; Barthwal, J. P.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 34, 9, 1984, 943-945
 Title:
            Synthesis of Some Substituted Benzodiazepines as Possible CNS
            Depressant Drugs
 Abstract:
            A new series of
            2,3-cyclopentano-3,4-dihydro-4-spirocyclopentano-1,5-benzodiazepine
            which are substituted in 5-position with b-N-heterocycloehtyl or
            g-N-heterocyclo-n-propyl groups have been synthesized and evaluated
            for their CNS depressant activity including anticonvulsant, analgesic
            and pentobarbital induced hypnosis.These compounds were also
            investigated for their ability to inhibit in vitro succinate dehydrogenase
            (SDH).In most of the compounds an appreciable CNS depressant
            activity has been found to be associated with the compounds
            possessing good SDH inhibitory activity.Low toxicity of these
            compounds was reflected by their high approximate LD50 values. - Key
            words: Benzodiazepines, pharmacology, synthesis, toxicity; CNS
            depressant drugs; Succinate dehydrogenase, inhibition
 CNR:
            5796437

 Author:
            Herz, A.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., GE, 34, 9a, 1984, 1080-1083
 Title:
            Role of Multiple Opioid Receptors and Corresponding Ligands in Pain
            Modulation
 Abstract:
            The multiplicity of opioid peptides (endorphins) present in the
            mammalian CNS finds a counterpart in the existence of various types
            of opioid receptors (m, d, c, e).The various receptor types, which
            possess distinctive relationships to particular opioid peptides, play a
            distinctive role in pain modulation.At the cerebral level premarily m-
            and probably e-receptors, rather than c-receptors appear to be
            involved, and, at the spinal level, primarily m- and c-receptors.The
            function of d-receptors at both levels remains unclear.There is certain
            evidence that the various opioid receptor types (and corresponding
            ligands) are of variable significance in the control of pain dependent
            upon the nature of the nociceptive stimulus (e.g. thermal vs. pressure).
            - Key words: Endorphins; Pain; Opioid receptors, role in pain
            modulation
 CNR:
            5796464

 Author:
            Hennies, H. H.; Hess, V.; Flohe, L.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 34, 11, 1984, 1481-1484
 Title:
            Antagonism by Supidimide of Haloperidol-induced Augmentation of
            <3H>-Spiperone Binding in Rat Striatum
 Abstract:
            Rats were treated for two weeks with haloperidol alone or with
            additional test drugs and the D2 receptor density in the striatum was
            investigated after a drug-free period of five days.The D2 receptor
            system as analysed by <3H>-spiperone binding was best
            characterized by a model with two binding sites of different affinity and
            the following constants: KDhigh = 0.13 nmol/l; KDlow = 5.8 nmol/l; Bmax
            high = 107 fmol/mg prot.; Bmax low = 598 fmol/mg prot.Chronic
            haloperidol treatment substantially augmented the total binding
            capacity primarily, if not exclusively, due to an increase of Bmax low.
            2-(2-Oxo-3-piperidyl)-1,2-benzisothiazoline-3-one-1,1-dioxide
            (supidimide), a functional synergist of neuroleptics in acute
            experiments, surprisingly antagonized the haloperidol-induced
            receptor augmentation, whereas other CNS depressants (diazepam
            and phenobarbital) were ineffective. - Key words: Dopamine, receptor;
            Haloperidol; Sedative drugs; Spiperone; Supidimide, pharmacology
 CNR:
            5832239

 Author:
            Philipsborn, G. v.; Gries, J.; Hofmann, H. P.; Kreiskott, H.; Kretzschmar,
            R.; et al.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 34, 11, 1984, 1489-1497
 Title:
            Pharmacological Studies on Propafenone and its Main Metabolite
            5-Hydroxypropafenone
 Abstract:
            1.The new antiarrhythmic drug propafenone and its main human
            metabolite 5-hydroxypropafenone were investigated for antiarrhythmic,
            local anaesthetic, Ca(++)-antagonistic and b-adrenoceptor blocking
            effects as well as for their activity on the central nervous sytem. 2.In
            isolated organs (guinea-pig atria, rat aortic strips)
            5-hydroxypropafenone had a smaller effect on the maximum following
            frequency, a greater negative inotropic effect, a greater Ca(++)-
            antagonistic effect and a very distinctly weaker b-adrenoceptor
            blocking effect than propafenone. 3.Consistent with its antiarrhythmic
            potency in vitro, intracutaneous 5-hydroxypropafenone had a smaller
            local anaesthetic effect in the guinea pig wheal. 4.In contrast to these
            findings 5-hydroxypropafenone showed a stronger antiarrhythmic
            potency in vivo (rat and dog), as demonstrated on the aconitine- and
            infarction arrhythmias.In addition, in His bundle studies
            5-hydroxypropafenone caused a more marked prolongation of the
            conduction time in atria, AV-node and His-Purkinje system.In vivo the
            b-adrenoceptor blocking effect of 5-hydroxypropafenone (isoprenaline
            tachycardia, rat) was smaller than that of propafenone. 5.The
            difference between the in vitro and in vivo potency of
            5-hydroxypropafenone may be explained by differences in
            pharmacokinetics, e.g. by a smaller distribution volume compared to
            propafenone. 6.CNS effects were investigated due to local anaesthetic
            properties of the substances tested.As indicator of CNS activity
            anticonvulsant effects, detectably beneath convulsion-inducing doses,
            were determined in rats (max. electroshock seizures).The results show
            low CNS activity of propafenone which is even lower for the metabolite
            but which is distinctly higher for lidocaine and - related to the
            antiarrhythmic potency - for flecainide, too.Studies for CNS side effects
            with simultaneous EEG and ECG recording in rabbits revealed that
            overdoses of propafenone and 5-hydroxypropafenone manifest
            themselves as ECG changes (2nd degree AV block; extrasystoles)
            while neurotoxic effects (EEG seizure patterns, visible clonism) may
            occur only after further drug administration.By contrast, toxic CNS
            symptoms following lidocaine overdosage are not preceded by
            marked ECG changes. - Key words: Antiarrhythmics;
            5-Hydroxypropafenone, mode of action, pharmacology; Propafenone,
            mode of action, pharmacology; Rytmonorm
 CNR:
            5832241

 Author:
            Yuge, T.; Hase, T.; Takayanagi, Y.; Kamasuka, T.; Amemiya, K.; Horiba, M.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 34, 11a, 1984, 1659-1667
 Title:
            Pharmacokinetic Studies of Mabuterol, a New Selective b2-Stimulant. I:
            Studies on the absorption, distribution and excretion in rats
 Abstract:
            Pharmacokinetic studies on absorption, distribution, excretion and
            placental transfer of the b-sympathomimetic 14C-labelled
            dl-1-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-tert.-butylamino-ethanol
            hydrochloride (mabuterol) have been carried out in rats.Mabuterol was
            easily absorbed from the whole length of the small intestine in a study in
            situ with the gastro-intestinal ligated loop technique.The blood and tissue
            levels of radioactivity reached the maximum within 1 h after oral
            administration.Concerning tissue distribution (excluding the digestive tract)
            after oral administration, the radioactivity in the liver, lung, kidney and
            several secretory organs was considerably higher than that in the
            blood.The levels of radioactivity in these tissues continued at almost the
            same levels for 2-6 h after oral administration, resulting from a slow gastric
            emptying of the radioactivity.The whole-body autoradiograms obtained
            after intravenous administration revealed the secretion of the radioactivity
            into the stomach.The radioactive concentration in the CNS was much
            lower than that in the principal organs with either route of
            administration.About 60percent and 26percent were excreted into urine
            and feces, respectively, within 24 h after oral administration.Although about
            22percent was excreted into bile within 24 h after intravenous
            administration, no other evidence of enterohepatic circulation was
            observed.The multiple oral administration of 14C-mabuterol indicated no
            appreciable accumulation in the tissues of rats.A placental transfer in the
            pregnant rats in the last stage of gestation was no significant. - Key words:
            Bronchodilators * b2-Mimetics * Mabuterol, absorption, distribution,
            excretion, pharmacokinetics, placental transfer
 CNR:
            5834503

 Author:
            Yamamoto, Jyunji; Haruno, Akihiro; Yoshimura, Yuji; Unemi, Norio;
            Kunimune, Yoshio; et al.
 Reference:
            Journal, JPMSAE, J.Pharm.Sci., EN, 73, 2, 1984, 212-214
 Title:
            Effect of Coadministration of Uracil on the Toxicity of Tegafur
 Abstract:
            The cardiotoxic and neurotoxic effects of tegafur, an anticancer agent,
            were compared with those of uracil plus tegafur (4:1 mol/mol) in mice,
            rats, rabbits, cats and dogs.Uracil plus tegafur was shown to be less
            toxic than the drug alone in all the species, and uracil was found to
            decrease the toxicity of tegafur. a-Fluoro-b-alanine, a catabolic
            metabolite of the drug, had toxic effects similar to tegafur.The results
            suggest that administration of uracil with tegafur prevents the side
            effects of the drug on the heart and CNS by inhibiting the degradation
            of 5-fluorouracil.
 CNR:
            5835805

 Author:
            Cotler, S.; Gustafson, J. N.; Colburn, W. A.
 Reference:
            Journal, JPMSAE, J.Pharm.Sci., EN, 73, 3, 1984, 348-351
 Title:
            Pharmacokinetics of Diazepam and Nordiazepam in the Cat
 Abstract:
            The cat has been used extensively as an experimental model for
            studying the pharmacology of compounds that exhibit CNS activity
            including diazepam and nordiazepam.However, since little is known
            about the distribution and elimination of diazepam in this species, the
            pharmacokinetics of diazepam and nordiazepam were studied in the
            cat following intravenous doses of 5, 10, and 20 mg/kg of diazepam
            and 5 and 10 mg/kg of nordiazepam.The disappearance of diazepam
            and nordiazepam from blood was fitted with classical equations.
            Theoretical and trapezoidal areas under the curve (AUCth and AUCtr)
            were calculated.The volumes of distribution (Vdb) were calculated as
            model-independent parameters for diazepam and
            nordiazepam.Intrinsic hepatic clearance, extraction ration, and tissue
            binding parameters were also calculated for diazepam.From the
            observed data, it is apparent that the blood concentrations and the
            resulting areas under the curves are proportional to the dose of
            diazepam administered and that the pharmacokinetics of diazepam
            were linear over the dose range studied.In addition, nordiazepam
            formed after diazepam administration appeared to be proportional to
            the dose of diazepam administered.The terminal elimination rate
            constant of nordiazepam remained constant over the dose range
            studied.It appears that both diazepam and nordiazepam are highly
            bound in tissue, The total body clearance of diazepam (4.72 +/- 2.45
            mL/min/kg) is approximately six times that of nordiazepam (0.85 +/-
            0.25 mL/min/kg).Approximately 50percent of an administered dose of
            diazepam was biotransformed to nordiazepam in the cat.
 CNR:
            5835840

 Author:
            Fink, C.; Hoelzl, J.; Rieger, H.; Krieglstein, J.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., GE, 34, 2, 1984, 170-174
 Title:
            Effects of Valtrate on the EEG of the Isolated Perfused Rat Brain
 Abstract:
            The purpose of the present investigation was to prove the central
            activity of valtrate.In order to avoid biotransformation of valtrate the
            isolated perfused rat brain was used for this study.The CNS activity of
            the drug was characterized by EEG changes which were analysed
            visually and quantified by automatic methods.The following results
            were obtained: 1.In the EEG of brains perfused with valtrate the normal
            backgroud beta activity was interrupted by spikes and paroxysmal
            patterns of theta frequencies. 2.These patterns disappeared after
            reperfusion with the control medium without drug. 3.Valtrate reduced
            the beta activity and produced an increase in the theta and delta
            frequencies of the EEG. 4.Using valtrate concentrations of 0.1-100
            mmol/l in the perfusion medium a clear dose-response relationship
            was not demonstrable. - Key words: Valepotriates; Valtrate, EEG
            analysis
 CNR:
            5867324

 Author:
            Horstmann, Michael
 Reference:
            Journal, JPPMAB, J.Pharm.Pharmacol., EN, 36, 1984, 770-771
 Title:
            Influence of mecamylamine and atropine on tolerance development to
            nicotine hypothermia in rats
 Abstract:
            Nicotine hypothermia is known as a central effect of nicotine waning
            after repeated administration due to the development of tolerance.In
            the present experiments using female rats, this tolerance was
            attenuated by the concomitant administration of
            mecamylamine.Atropine was without effect.It is concluded that
            tolerance to this effect of nicotine implies its contact with specific sites
            within the cns.
 CNR:
            5941827

 Author:
            Wazer, David E.; Rotrosen, John
 Reference:
            Journal, JPPMAB, J.Pharm.Pharmacol., EN, 36, 1984, 853-854
 Title:
            Murine lymphocytes lack clearly defined receptors for muscarinic and
            dopaminergic ligands
 Abstract:
            <3H>Quinuclidinyl benzilate and <3H>spiperone binding to murine
            lymphocytes is displaceable but differs from binding to brain receptor
            sites for these ligands: (1) binding to intact lymphocyte preparations
            was not saturable; (2) disruption of intact lymphocytes was associated
            with a marked loss of displaceable ligand binding; (3) drugs
            differentially displace these ligands in lymphocytes compared to
            brain.Displaceable binding was increased following incubation of
            lymphocytes under phospholipid methylating conditions; however,
            marked effects on cell viability and cell recovery make it difficult to
            interpret these binding changes.If dopaminergic and cholinergic
            receptors do exist on lymphocytes, their binding characteristics are
            profoundly different from comparable cns receptors.
 CNR:
            5941851

 Author:
            Govoni, S.; Petkov, V. V.; Montefusco, O.; Missale, C.; Battaini, F.; et al.
 Reference:
            Journal, JPPMAB, J.Pharm.Pharmacol., EN, 36, 1984, 458-460
 Title:
            Differential effects of caffeine on dihydroxyphenylacetic acid
            concentrations in various rat brain dopaminergic structures
 Abstract:
            The behavioural and neurochemical effects of caffeine were examined
            in rats.The intraperitoneal administration of different doses of caffeine
            significantly decreased DOPAC concentrations in striatum,
            hypothalamus and frontal cortex, but increased them in nucleus
            accumbens.These observations suggest that the effect of caffeine on
            the central nervous system (cns) are at least partially mediated through
            an interaction with the dopaminergic system.
 CNR:
            5942236

 Author:
            Bianchi, G.; Fiocchi, R.; Peracchia, F.; Petrillo, P.; Tavani, A.; Manara,
            L.
 Reference:
            Journal, JPPMAB, J.Pharm.Pharmacol., EN, 36, 1984, 326-330
 Title:
            The peripheral narcotic antagonist N-allyl levallorphan-bromide (CM
            32191) selectively prevents morphine antipropulsive action and
            buprenorphine in-vivo binding in the rat intestine
 Abstract:
            The assumed low ability of the quaternary narcotic antagonist N-allyl
            levallorphan-bromide (CM 32191) to cross the blood-brain barrier and
            its selectivity in relieving the peripherally-elicited antipropulsive action
            of morphine while preserving analgesia has been tested.To ascertain
            the extent of penetration of CM 32191 into the cns, its relative potency
            in preventing the in-vivo binding of high specific activity
            <3H>buprenorphine in the rat cns and small intestine was
            compared.Pretreatment was with CM 32191 at 16, 30 or 60 mg kg-1
            s.c., 20, 60 or 120 min before buprenorphine, the concentrations of
            which in cerebrum and spinal cord were comparable with control
            values, but were consistently reduced in the intestine (longitudinal
            muscle with attached myenteric plexus).Pretreatment with naloxone
            (20 min, 0.5 or 1 mg kg-1 s.c.) lowered buprenorphine binding in
            intestine and cns.Neither narcotic antagonist produced significant
            changes in buprenorphine plasma concentrations.The peripheral
            selectivity of CM 32191, methyl naloxone and naloxone was examined
            by investigating in the same rats nociception in the hot plate (central
            opiate-sensitive mechanism) and the transit of a charcoal meal along
            the small intestine (local opiate-sensitive mechanism).Both effects
            were inhibited by morphine (5 mg kg-1 i.v.).Naloxone (10 min
            pretreatment, 0.5 or 1 mg kg-1 s.c.) did not selectively antagonize
            intestinal action of the morphine since the relief of charcoal transit
            inhibition was consistently associated with complete loss of
            analgesia.Pretreatment (s.c. at 50 min) with the N-methyl quaternary
            analogue of naloxone, at low doses only, selectively prevented the
            slowing of transit by morphine without significantly impairing its
            antinociceptive action; higher doses (>16 mg kg-1) suppressed the
            antinociceptive action.In contrast, CM 32191 (16, 30 or 60 mg kg-1, 10,
            50 or 110 min before morphine) always selectively antagonized
            constipation induced by the opiate and did not influence its action
            delaying hot-plate reaction.
 CNR:
            5942309

 Author:
            Christensen, J. A.; Engelstoft, M.; Schaumburg, K.; Schou, H.; Watjen, F.
 Reference:
            Journal, TELEAY, Tetrahedron Lett., EN, 24, 46, 1983, 5151-5152
 Title:
            ON THE FORMATION OF THE 1-AZA-(3.1.1)-BICYCLOHEPTANE
            RING SYSTEM
 Abstract:
            The preveously unpublished bicyclic system
            1-aza-(3.1.1)-biycyloheptane has been shown to exist as an
            unexpected intermediate in the synthesis of Femoxetine, a CNS active
            drug.
 CNR:
            5549822

 Author:
            Chen, Wen-Yean; Gilman, Norman W.
 Reference:
            Journal, JHTCAD, J.Heterocycl.Chem., EN, 20, 1983, 663-666
 Title:
            Synthesis of 7-Phenylpyrimido<5,4-d><l>benzazepin-2-ones (1)
 Abstract:
            The syntheses of the 7-phenylpyrimido<5,4-d><l>benzazepin-2-ones
            3, 4, and 5 are described.The 7-phenyl group was introduced by
            phenylation of the lactam nitrogen in 10, 13 and 16 respectively.One of
            these compounds, 5, showed moderate activity as a CNS agent.
 CNR:
            5558356

 Author:
            Earley, James V.; Fryer, R. Ian; Gilman, Norman W.
 Reference:
            Journal, JHTCAD, J.Heterocycl.Chem., EN, 20, 1983, 1195-1197
 Title:
            2-Benzazepines. 7. Synthesis of Pyrimido<5,4-d>benzazepines
 Abstract:
            The novel syntheses of pyrimido<5,4-d>benzazepines are
            described.The first synthesis started with 3-phenylphthalide which in
            three steps was converted to a functionalized pyrimidine which was
            cyclized to give the 2-benzazepine ring system.The second approach
            used o-benzoylbenzoic acid methyl ester as the starting material,
            which in four steps was converted to a functionalized pyrimidine which
            was cyclized to give a
            2-benzazepine.Pyrimido<5,4-d><2>benzazepines have been found to
            have activity in standard central nervous system (CNS)
            pharmacological tests.
 CNR:
            5559282

 Author:
            Valenta, Vladimir; Nemec, Jiri; Protiva, Miroslav
 Reference:
            Journal, CCCCAK, Collect.Czech.Chem.Commun., EN, 48, 4, 1983,
            1089-1096
 Title:
            BASIC AMIDES OF 2,4,5-TRICHLOROPHENOXYACETIC,
            2,4,6-TRIMETHYLPHENOXYACETIC AND
            4-BROMO-3,5-DIMETHYLPHENOXYACETIC ACID AND SOME
            RELATED COMPOUNDS; SYNTHESIS AND PHARMACOLOGICAL
            SCREENING
 Abstract:
            Reaction of methyl esters II of 2,4,5-trichlorophenoxyacetic (Ia),
            2,4,6-trimethylphenoxyacetic (Ib) and
            4-bromo-3,5-dimethylphenoxyacetic acid (Ic) with
            2-diethylaminoethylamine, 2-morpholinoethylamine,
            3-morpholinopropylamine, 1-methylpiperazine,
            3-(4-methylpiperazino)propylamine,
            3-<4-(2-tolyl)piperazino>propylamine and
            1,4-bis(3-aminopropyl)piperazine in boiling ethanol gave the basic
            amides Va-XIc which were isolated as hydrochlorides.Reactions of the
            acid chlorides IVa and IVb with 1,4-bis(2-hydroxyethyl)piperazine and
            1,4-bis(3-hydroxypropyl)-piperazine in dimethylformamide resulted
            directly in dihydrochlorides of diesters XIIab and XIIIab.The
            compounds prepared have only weak CNS effects (mostly of the
            depressant type); they have local anaesthetic, mild hypotensive (some
            of them adrenolytic), antiarrhythmic and peripheral vasodilating
            activities.
 CNR:
            5561060

 Author:
            Valenta, Vladimir; Holubek, Jiri; Svatek, Emil; Dlabac, Antonin;
            Bartosova, Marie; Protiva, Miroslav
 Reference:
            Journal, CCCCAK, Collect.Czech.Chem.Commun., EN, 48, 5, 1983,
            1447-1463
 Title:
            a-(4-TOLYL)DOPAMINE, DERIVATIVES AND ANALOGUES;
            SYNTHESIS AND PHARMACOLOGICAL SCREENING
 Abstract:
            The ketone XIII, obtained by Friedel-Crafts reaction of toluene with
            homoveratroyl chloride, was converted by the Leuckart reaction to the
            formamido derivative IXb which was used as the starting product for
            the synthesis of amines IIIb-Vb.Reduction of the ketone XIII gave the
            alcohol XVI which was treated with hydrogen chloride and afforded the
            chloro compound XVII.Its substitution reactions with
            1-methylpiperazine, 1-(2-hydroxyethyl)piperazine and
            1-phenylpiperazine resulted in the piperazines VIb-VIIIb.Acylations of
            the amine IIIb with acetic anhydride and homoveratroyl chloride gave
            the amides Xb and XIb which, together with the formamide IXb, were
            subjected to the Bischler-Napieralski reaction.
            3,4-Dihydroisoquinolines XXII-XXIV were obtained and reduced to the
            1,2,3,4-tetrahydroisoquinolines XXVb-XXVIIb.Treatment of XXVIIb
            with formaldehyde afforded the berbine derivative
            XXVIII.Demethylation of the amine IIIb with hydrobromic acid resulted
            in the title compound IIIa.Similar demethylations of the
            dimethoxyamines IVb-VIIIb, XXVb and XXVIb led to the
            dihydroxyamines IVa-VIIIa, XXVa and XXVIa which are dopamine
            derivatives.Reaction of Va with benzoyl chloride gave the dibenzoate
            XXX.The CNS activities of the compounds prepared are of a low
            degree.Several of them (IIIa-VIa, IIIb-Vb,XXVb) show in higher doses
            signs of central stimulant action but only for compound IVa an
            antireserpine effect was proven.The expected anticataleptic activity
            was found only in a low degree with compound VIIIa; on the contrary,
            compounds IIIa and XXVa are procataleptogenic.Some compounds
            (IIIa, IXb, XXVI, XXVIII) potentiated thiopental.In single cases local
            anaesthetic, spasmolytic, hypotensive, hypertensive, hypoglycaemic,
            diuretic and antiarrhythmic effects were observed.
 CNR:
            5561096

 Author:
            Polivka, Zdenek; Holubek, Jiri; Svatek, Emil; Dlabac, Antonin; Pucek, Dusan; et al.
 Reference:
            Journal, CCCCAK, Collect.Czech.Chem.Commun., EN, 48, 5, 1983, 1465-1476
 Title:
            3-(4-METHYLPIPERAZINO)DIBENZO<b,f>-1,2,4-TRIAZOLO<4,3-d>-1,4-THIAZEPINE
            AND ITS 6-CHLORO AND 12-CHLORO DERIVATIVES; SYNTHESIS AND
            PHARMACOLOGY
 Abstract:
            Dibenzo<b,f>-1,4-thiazepin-11(10H)-ones IIa-IIc reacted with phosphorus pentasulfide
            in pyridine under the formation of the thiones IIIa-IIIc which were transformed by
            treatment with hydrazine hydrate in 1-butanol to the hydrazine derivatives
            IVa-IVc.Reactions with triethyl orthoformate in ethanol in the presence of sulfuric acid
            effected cyclization to dibenzo<b,f>-1,2,4-triazolo<4,3-d>-1,4-thiazepine (Va) and its
            chloro derivatives Vb, Vc which were treated with bromine in a boiling mixture of
            chloroform and pyridine and gave the 3-bromo derivatives VIa-VIc.The title compounds
            Ia-Ic were obtained by substitution reactions with an excess of boiling
            1-methylpiperazine.An attempt at preparing an analogous
            14H-dibenzo<b,g>-1,2,4-triazolo<4,3-d>-1,4-thiazocine derivative was discontinued in
            the stage of reaction of the thione X with hydrazine hydrate which resulted in the azine
            XI.Compounds Ia-Ic on intravenous administration are highly toxic and inactive in tests
            for CNS effects; compound Ic showed a clear anticholinergic activity.
 CNR:
            5561097

 Author:
            Walser, A.; Flynn, T.; Fryer, R.I.
 Reference:
            Journal, JHTCAD, J.Heterocycl.Chem., EN, 20, 1983, 791-793
 Title:
            Quinazolines and 1,4-benzodiazepines. XCIV (1).
            Pyrazino<1,2-a><1,4>benzodiazepines
 Abstract:
            A series of pyrazino<1,2-a><1,4>benzodiazepines were prepared by
            acylating the primary amino group of an
            a-amino-1,4-benzodiazepine-2-ylideneacetic acid ester (1) with
            a-chloroacyl chlorides followed by cyclodehydrohalogenation with
            triethylamine in dimethylformamide.Some pharmacological data for
            CNS-activity are discussed.
 CNR:
            5563987

 Author:
            Gupta, K. A.; Saxena, Anil K.; Jain, Padam C.; Dua, P. R.; Prasad, C.
            R.; Anand, Nitya
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, <B> 22, 8, 1983, 789-794
 Title:
            Synthesis and Biological Activity of 2,6-disubstituted
            3-Aryl-4(3H)-pyrimidones as Potential CNS Agents
 Abstract:
            The reaction of N-arylamidines (III) with appropriate 2-alkynoic ester
            gives 2,6-disubstituted 3-aryl-4(3H)-pyrimidones (IV) in one step
            except in the reaction of
            N-(2-trifluoromethylphenyl/biphenyl)-S-methylisothiourea with ethyl
            propiolate, where the required pyrimidones (IVa17/IVa20) along with the
            adduct (Va/Vb) have been isolated; these adducts on cyclisation yield
            the corresponding pyrimidinones (IVa17/IVa20).
            2,3,6-Triphenyl-4(3H)-pyrimidone (IVh1) on treatment with P2S5
            furnishes the corresponding thione (VI).Some of these compounds
            have shown significant central muscle relaxant, hypnotic,
            anticonvulsant, CNS depressant, antiinflammatory and diuretic
            activities.
 CNR:
            5574123

 Author:
            Varma, Rajendra S.; Chauhan, Sudha; Prasad, C. R.
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 22, 7, 1983, 705-706
 Title:
            Synthesis of Some
            3-<4-(p-Carbalkoxyphenylcarbamoyl)phenylaminomethyl>benzothiazolin-2-thiones
            and Related Systems as CNS Active Agents
 Abstract:
            The title compounds (I-III) have been synthesized by Mannich reaction on
            benzothiazolin-2-thione, benzimidazolin-2-thione and benzoxazolin-2-one with alkyl
            (N-4'-aminobenzoyl)-4-aminobenzoates.N-(4'-Nitrobenzoyl)-4-aminobenzoic acid
            hydrazide reacts with salicylaldehyde in ethanol containing a few drops of gl. acetic
            acid to give 4-(4'-nitrobenzoylamino)benzoic acid salicylidenehydrazide (IV).
 CNR:
            5576078

 Author:
            Shridhar, D. R.; Sastry, C. V. Reddy; Bansal, O. P.; Rao, P. Pulla
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 22, 3, 1983, 297-299
 Title:
            Antiinflammatory Agents : Part VIII - Synthesis of Some
            3-Aryl-2H-1,4-benzoxazine-6-alkanoic Acids and Methyl
            4-(6-chloro-/6-nitro-2H-1,4-benzoxazin-3-yl)phenylacetates
 Abstract:
            A number of ethyl 3-aryl-2H-1,4-benzoxazine-6-acetates (4a-c) and
            -6-a-methylacetates (4d-f) 3-aryl-2H-1,4-benzoxazine-6-acetic acids
            (5a-c) and -6-a-methylacetic acids (5d-f) and methyl 4-(6-chloro- and
            -6-nitro-2H-1,4-benzoxazin-3-yl)phenylacetates (6 and 7) have been
            synthesized and evaluated for their antiinflammatory and other CNS
            activities.
 CNR:
            5576501

 Author:
            Agarwal, Rajesh; Chaudhary, Chapla; Misra, V. S.
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 22, 3, 1983, 308-310
 Title:
            Synthesis of
            2-Aryl-1-(4-morpholinophenyl)-4-(3,4-disubstituted-benzylidene)imidazolin-5-ones
            as CNS Active Agents
 Abstract:
            The title compounds (IVa-l) have been prepared by the action of
            p-morpholinoaniline (II) on appropriate oxazolin-5-ones (III) in the presence of
            anhyd.ZnCl2 or super dry pyridine.However, the interaction of II and III in ordinary
            pyridine/benzene or in the absence of anhydr.ZnCl2 gives
            p-morpholinophenylcarboxamides (V) of a-arylcarboxamido-b-(3,4-disubstituted
            phenyl)acrylic acids indicating the reaction of II and III to be moisture
            sensitive.Compounds IV have been found to be nontoxic and psychotropic.
 CNR:
            5576505

 Author:
            Shridhar, D. R.; Sastry, C. V. Reddy; Bansal, O. P.; Rao, Pulla; Singh,
            P. P.; et al.
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 22, 12, 1983, 1236-1242
 Title:
            Synthesis & Pharmacology of Some New Oxime Ethers & Alkanoic
            Acid Derivatives Derived from 6-Acetyl-2H-1,4-benzoxazin- /SUB>
            -benzothiazin-3(4H)-ones
 Abstract:
            A large number of
            4-methyl/ethyl-2H-1,4-benzoxazin-3(4H)-one-6-acetoxime ethers
            (11-34), 4-methyl/ethyl-2H-1,4-benzothiazin-3(4H)-one-6-acetoxime
            ethers (35-58) and 6-acetyl-2H-1,4-benzoxazin-3(4H)-one-4-alkanoic
            acids and esters (59-64) have been synthesized and screened for their
            pharmacological activities.Some of these compounds have been
            found to exhibit moderate antiinflammatory activity, while several of
            them showed mild CNS depressant, central muscle relaxant and
            hypothermic activities.
 CNR:
            5577278

 Author:
            Girard, Yves; Atkinson, Joseph G.; Belanger, Patrice C.; Fuentes, Jose
            J.; Rokach, Joshua; et al.
 Reference:
            Journal, JOCEAH, J.Org.Chem., EN, 48, 19, 1983, 3220-3234
 Title:
            Synthesis, Chemistry, and Photochemical Substitutions of
            6,11-Dihydro-5H-pyrrolo<2,1-b><3>benzazepin-11-ones
 Abstract:
            A series of 6,11-dihydro-5H-pyrrolo<2,1-b><3>benzazepin-11-ones, 4,
            has been prepared as intermediates for potential CNS
            drugs.Substituents in the pyrrole ring of 4 were introduced by
            Friedel-Crafts cyclization of pyrrole-substituted
            1-(2-phenethyl)pyrrole-2-carboxylic acid derivatives (6) and by
            electrophilic substitution on the parent ketone 4a.Substituents in the
            benzene ring of 4 were introduced by Friedel-Crafts cyclization of
            substituted 2-(2-pyrrol-1-ylethyl)benzoic acids (12).Novel and efficient
            photochemical reactions were discovered for the direct introduction of
            the cyano and trifluoromethyl groups into the pyrrole ring of 4a.The
            latter reaction was extended to yield a series of trifluoromethylated
            heterocycles.
 CNR:
            5579198

 Author:
            Baronnet, Rene; Callendret, Raymond; Blanchard, Louisette;
            Foussard-Blanpin, Odette; Bretaudeau, Jean
 Reference:
            Journal, EJMCA5, Eur.J.Med.Chem.Chim.Ther., FR, 18, 3, 1983,
            241-247
 Title:
            Synthese et pharmacodynamie de dialkylamino-3 1H,3H
            quinazolinediones-2,4 et de derives
 Abstract:
            Synthesis of 3-dialkylamino-1H,3H-quinazoline-2,4-diones are
            reported.These compounds exhibit a CNS sedation, a diuretic effect
            and an antihypertensive activity with an a-adrenolytic
            component.Structure-activity relationships are discussed.Key-words:
            Dialkylamino-3 1H,3H quinazolinediones-2,4. - Sedatifs. - Diuretiques.
            - Antihypertenseur. - a-adrenolytique.
 CNR:
            5608256

 Author:
            Vierfond, Jean-Michel; Lehuede, Jacques; Miocque, Marcel
 Reference:
            Journal, EJMCA5, Eur.J.Med.Chem.Chim.Ther., FR, 18, 1, 1983,
            35-40
 Title:
            Aminomethylation de la phenothiazine et de la phenoxazine. Etude
            chimique et pharmacologique
 Abstract:
            Phenothiazine and phenoxazine are converted to aminomethyl
            derivatives in position 3 or 3 and 7.Experimental conditions for mono
            or disubstitutions, and structure of products are studied.A 1-substituted
            derivative of phenothiazine is described.Pharmacological screening of
            main derivatives of phenothiazine shows low activity on CNS, small
            inhibition of staphylococcus and colibacillus but no parasiticidal
            action.Key-words: Aminomethylation. - Phenothiazine. - Phenoxazine.
            - Systeme nerveux central.
 CNR:
            5608271

 Author:
            Balsamo, Aldo; Lapucci, Annalina; Macchia, Bruno; Macchia, Franco;
            Passerini, Norina
 Reference:
            Journal, EJMCA5, Eur.J.Med.Chem.Chim.Ther., EN, 18, 6, 1983,
            563-566
 Title:
            Short Communication. Synthesis and Pharmacological Activity of
            1-Phenyl-2-oxa-5-azabicyclo<4.4.0>decane derivatives
 Abstract:
            Some 1-phenyl-2-oxa-5-azabicyclo<4.4.0>decane derivatives have
            been synthesized and screened for their activity on the Central
            Nervous System.Generally all compounds showed both CNS exciting
            and anticonvulsant activity.Configurational and conformational studies
            of the bicyclic amides 9, 10, and 15 have been carried out by means of
            1H NMR spectroscopy.Key-words:
            1-Phenyl-2-oxa-5-azabicyclo<4.4.0>decane derivatives. - Central
            nervous system (activity). - Anticonvulsant activity.
 CNR:
            5611103

 Author:
            Martino, Giovanni De; Massa, Silvio; Corelli, Federico; Panteleoni, Giancarlo; Fanini, Donatella;
            Palumbo, Giancarlo
 Reference:
            Journal, EJMCA5, Eur.J.Med.Chem.Chim.Ther., EN, 18, 4, 1983, 347-350
 Title:
            C.N.S. agents : neuropsychopharmacological effects of 5H-pyrrolo<2,1-c> <1,4>benzodiazepine
            derivatives
 Abstract:
            Some derivatives of 5H-pyrrolo<2,1-c><1,4>benzodiazepine were evaluated as central nervous
            system agents by several screening tests on mice
            ;5,11-dioxo-11a-ethoxycarbonyl-1,10,11,11a-tetrahydro-5H-pyrrolo<2,1-c><1,4>benzodiazepine
            is the most interesting compound.The target substances were prepared starting from the
            reaction between 2-nitrobenzoylaminomalonate (or the 5-chloroanalogue) and acrylic aldehyde.
            Keywords : Benzodiazepine derivatives. - Pyrrolobenzodiazepines. - CNS agents. -
            Neuropsychopharmacological effects.
 CNR:
            5611485

 Author:
            Ong-Lee, Avelina; Sylvester, Leo; Wasley, Jan W. F.
 Reference:
            Journal, JHTCAD, J.Heterocycl.Chem., EN, 20, 1983, 1565-1569
 Title:
            Synthesis of
            1,3,4,14b-Tetrahydro-2H,10H-pyrazino<1,2-a>pyrrolo<2,1-c><1,4>benzodiazepines
 Abstract:
            1,3,4,14b-tetrahydro-2H,10H-pyrazino<1,2-a>pyrrolo<2,1-c><1,4>benzodiazepines
            (1a-e) were synthesized to investigate their potential CNS activity.The key step in
            the synthesis was the formation of the
            10,11-dihydro-5H-pyrrolo<2,1-c><1,4>benzodiazepine (13) by the reduction and
            concomitant cyclization of the nitroketone (11).Biological evaluation of 1a-e
            revealed interesting properties for 1b (CGS 7525A).
 CNR:
            5632098

 Author:
            Press, Jeffery B.; Eudy, Nancy H.
 Reference:
            Journal, JHTCAD, J.Heterocycl.Chem., EN, 20, 1983, 1593-1596
 Title:
            Synthesis of 2-Phenyl-3,4-dihydro-2H- and
            -3,4,5,6-tetrahydro-2H-1,6-benzothiazocine Derivatives
 Abstract:
            The resynthesis of 2-phenyl-3,4-dihydro-2H-benzothiazocin-5(6H)-one
            (1) was investigated in order to prepare derivatives with potential CNS
            activity.Lactam 1 could be converted to amidine derivatives 6a-e via
            the intermediacy of the thioether 5a.Reduction of 1 with lithium
            aluminum hydride gave amine 8a.Reductive alkylation of 8a gave 9a
            and 9b while acylation of 8a gave derivatives 10a-d.No interesting
            biological properties were found for these compounds.
 CNR:
            5632104

 Author:
            Dugas, H.; Spino, C.; Ouellette, M.
 Reference:
            Journal, CJCHAG, Can.J.Chem., EN, 61, 1983, 2540-2543
 Title:
            Synthesis of spin-labeled analogues of drug molecules with potential
            action on neuroreceptors
 Abstract:
            The syntheses of novel spin-labeled analogues of butaclamol, a
            spin-labeled phenylaziridinium and two amino derivatives of
            butaclamol, are presented.Preliminary results of in vitro activity of
            these compounds on dopaminergic, and adrenergic receptors
            correlate with the importance of the previously proposed lipophilic
            accessory binding site in CNS dopamine receptor.
 CNR:
            5668558

 Author:
            Yamada, Yoshihisa; Otsuka, Minezo; Tani, Junichi; Oine, Toyonari
 Reference:
            Journal, CPBTAL, Chem.Pharm.Bull., EN, 31, 4, 1983, 1158-1165
 Title:
            Synthesis of the Metabolites of Afloqualone and Related Compounds
 Abstract:
            Seven main metabolites (3-9) of afloqualone
            (1,6-amino-2-fluoromethyl-3-(o-tolyl)-4(3H)-quinazolinone and related
            4(3H)-quinozolinone derivatives were synthesized.The metabolites 4
            and 5 containing a sulfur atom were prepared by the reaction of
            6-acetamido-2-chloromethyl-3-(o-tolyl)-4(3H)-quinazolinone (11) with
            NaSCH3 followed by oxidation with H2O2.Reaction of 11 and
            N-acetyl-L-cysteine gave the mercapturic acid-conjugated metabolite
            6.Condensation of 2-fluoroacetamido-5-nitrobenzoic acid (19) and
            2-aminobenzyl alcohol (20) with dicyclohexylcarbodiimide (DCC) in
            the presence of 1-hydroxy-benzotriazole afforded
            2-fluoromethyl-3(o-hydroxymethylphenyl)-6-nitro-4(3H)-quinazolinone
            (21), which was converted to the metabolites 7 and 8.Treatment of the
            2-bromomethyl-4(3H)-quinazolinone (24) with AgBF4*H2O in
            dimethylsulfoxide (DMSO) gave the 2-hydroxymethyl metabolite
            9.None of the main metabolites (2-9) showed significant central
            nervous system depressant activity.Keywords - afloqualone;
            6-amino-2-fluoromethyl-3-(o-tolyl)-4-(3H)-quinazolinone; metabolite of
            afloqualone; 4(3H)-quinazolinone; oxidation of sulfide; CNS
            depressant activity
 CNR:
            5673092

 Author:
            Avramova, P.; Dryanovska, L.; Ilarionov, Y.
 Reference:
            Journal, PHARAT, Pharmazie, EN, 38, 7, 1983, 443-444
 Title:
            Synthesis and Pharmacological Assessment of Carbamic and
            Carbonic Acid Esters with 1-Aryl-3-dimethylamino-1-propanols
 Abstract:
            The synthesis and results of the pharmacological assessment of new
            carbamic and carbonic acid esters with a stimulatory effect on the CNS
            are described.The structural analogues of carbamic acids are less
            toxic as compared to imipramine and to the respective derivatives of
            carbonic acid, and are also more active pharmacologically than some
            of the screening tests for antidepressant action.According to the test of
            antagonizing reserpine-induced hypothermia, the compounds coded
            3a, 4a, 4c, 4d exert a stronger effect by comparison with that of
            imipramine.
 CNR:
            5685906

 Author:
            Kar, A.
 Reference:
            Journal, PHARAT, Pharmazie, EN, 38, 5, 1983, 313-315
 Title:
            Synthesis and CNS-Depressant Profile of 3,4,5-Trimethoxybenzoyl
            Analogues
 Abstract:
            A series of 3,4,5-trimethoxybenzoyl analogues with varying electronic
            and stereochemical characteristics has been synthesized.Many of
            these compounds (4, 5, 9, 12, 15) showed appreciable potentiation of
            pentobarbitone-induced hyponsis.Several analogues (1, 5, 6, 11, 12,
            15) exhibited marked reduction of Spontaneous motor activity (SMA).
 CNR:
            5689481

 Author:
            Satsangi, R. K.; Zaidi, S. M. M.; Misra, V. S.
 Reference:
            Journal, PHARAT, Pharmazie, EN, 38, 5, 1983, 341-342
 Title:
            1-(4-Substituted-thiazol-2-yl)hydantoins as Anti-inflammatory and
            CNS-Active Agents
 Abstract:
 CNR:
            5689490

 Author:
            Harris, Alan; Middlemiss, David; Mills, Keith; Gower, Alma J.; Tyers,
            Michael B.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 26, 1, 1983, 55-60
 Title:
            Synthesis of exo-3-Phenylbicyclo<3.2.1>oct-3-en-2-amine and
            Related Compounds as Potential Analgesics
 Abstract:
            Several analogues (21 and 29-50) of
            exo-3-phenylbicyclo<3.2.1>oct-3-en-2-amine (1) were prepared, a
            compound that had been found to have marked antinociceptive activity
            in the inflamed-paw pressure test in rats.Two synthetically versatile
            methods leading to these compounds are described.In this series,
            antinociceptive activity increases with increasing size of the amine
            substituent, reaching an optimum with N(Me)Et (32), but this is always
            associated with central nervous system (CNS) stimulant activity.The
            antinociceptive activity of these compounds is most likelydue to an
            action that is similar to that of amphetamine rather than to an
            interaction with an opiate receptor.The endo diastereoisomer 22 and
            the benzo analogue 11 were both devoid of antinociceptive and CNS
            stimulant activity
 CNR:
            5701662

 Author:
            Sathi, G.; Gujrati, V. R.; Nath, C.; Agarwal, J. C.; Bhargava, K. P.;
            Shanker, K.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 33, 9, 1983, 1218-1221
 Title:
            Newer Formazans and Tetrazolium Indoles as Potential CNS-active
            Agents
 Abstract:
            Some new 2-aryl-5-(3'-indole)-3'-substituted phenyl tetrazolium
            bromide/iodide salts (IV) were synthesized by the oxidation of
            1-aryl-3-(3'-indole)-5-substituted phenyl formazans (III).These
            compounds III and IV were evaluated for their monoamine oxidase
            (MAO) inhibitory activity in vitro and various CNS activities in
            vivo.Several compounds exhibited promising CNS activities, III-b
            being the most active member of the present series showing marked
            antidepressant and MAO inhibitory activities and having low toxicity. -
            Key words: CNS-active agents; Formazan, derivatives, pharmacology,
            synthesis; Tetrazolium indole, derivatives, pharmacology, synthesis
 CNR:
            5733199

 Author:
            Trybulski, E.J.; Benjamin, L.; Vitone, S.; Walser, A.; Fryer, R. Ian
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 26, 3, 1983, 367-372
 Title:
            2-Benzazepines. 4. <1,2,3>Triazolo<4,5-d>benzazepines and
            Dibenzo<c,f><1,2,3>triazolo<3,4-a>azepines: Synthesis and
            Evaluation as Central Nervous System Agents
 Abstract:
            The facile synthesis of <1,2,3>triazolo<4,5-d><2>benzazepines and
            dibenzo<c,f><1,2,3>triazolo<3,4-a>azepines by the addition of sodium
            azide to acetylenic benzophenones is described.Examination of the
            pharmacological data indicates that selected triazolobenzazepines are
            as potent as diazepam in the anti-pentylenetetrazole test and are
            weaker in the inclined screen and rotarod tests, suggesting that these
            compounds have antianxiety properties similar to diazepam with fewer
            deficits in motor coordination.In addition, a possible diazepam
            antagonist was found in the triazolobenzazepine series. The
            diabenzotriazoloazepines were found to be inactive in four standard
            CNS screening procedures.
 CNR:
            5748117

 Author:
            Eiden, Fritz; Gerstlauer, Carmen; Buchhorn, Helga
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), GE, 316, 4, 1983,
            326-334
 Title:
            Tetrahydrocannabinol-Derivatives, Synthesis and Pharmacological
            Examination
 Abstract:
            The 2- and 4-formyl-THC-derivatives 2 and 3, as well as the
            azomethines, nitriles, phosphonates and stilbenes synthesized from 2
            and 3, were tested for CNS activity in the mouse.The oxime 4 and the
            nitrile 8 significantly decreased the spontaneous motility of mice.
 CNR:
            5748399

 Author:
            Sathi, Garima; Gujrati, Vibha R.; Sharma, Manju; Nath, Chandishwar;
            Bhargava, Krishna P.; Shanker, Kirpa
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), EN, 316, 9, 1983,
            767-772
 Title:
            New Quinolines as Potential CNS Agents
 Abstract:
            The compounds 1a-1l and 2a-2m were synthesized by condensation
            of various aryl-1-(4-aminophenyl)piperazines and substituted
            piperidines with substituted 4-chloroquinolines.The compounds were
            screened for their monoamine oxidase (MAO) inhibitory activites (in
            vitro) and various CNS activities (in vivo).Some compounds showed
            promising MAO inhibitory and antidepressant activites.The compounds
            did not produce acute neurological deficits and have low
            toxicity.Compounds 1b is the most active member of the
            series.Structure-activity relationships are discussed.
 CNR:
            5748473

 Author:
            Knabe, Joachim; Buech, Horst P.; Schmitt, Wolfgang
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), GE, 316, 12, 1983,
            1051-1053
 Title:
            Derivatives of Barbituric Acid, XXXV: Cytostatic and CNS Activities of
            Chiral Barbiturate Mannich Bases
 Abstract:
 CNR:
            5748618

 Author:
            Zaugg, Harold E.; Kyncl, Jaroslav
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 26, 2, 1983, 214-217
 Title:
            New Antihypertensive Cannabinoids
 Abstract:
            A number of azacannabinoids containing hydroxyacyl and aminoacetyl
            substituents on the nitrogen atom were synthesized.The hydroxyacetyl
            and g-hydroxybutyryl derivatives (4a and 7b, respectively) were potent
            antihypertensive agents (minimum effective dose, 3-5 mg/kg, orally) of
            the same order of activity as the highly CNS-active N-propargyl
            derivatives Ia and Ib.Furthermore, 4a showed weak stimulant
            properties at hypotensive dose levels, in contrast to the strongly
            CNS-depressant action characteristic of the N-propargyl analogues
            (Ia,b).
 CNR:
            5775654

 Author:
            Lee, Cheuk-Man; Zaugg, Harold E.; Michaels, Raymond J.; Dren, Anthony T.; Plotnikoff, Nicholas P.; Young, Patrick R.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 26, 2, 1983, 278-280
 Title:
            New Azacannabinoids Highly Active in the Central Nervous System
 Abstract:
            Pursuit of the hypothesis that optimum central nervous system (CNS) activity in 2-azacannabinoids (I and II) requires a
            moderately basic nitrogen atom (pK = 5-7) has led to several very active a-amino amide derivatives, namely,
            10-hydroxy-N,5,5-trimethyl-8-(1,2-dimethylheptyl)-1,2,3,4-tetrahydro-5H-<1>benzopyrano<4,3-c>pyridine-2-acetamide (3a),
            8-<5-(4-fluorophenyl)-2-pentyl>-10-hydroxy-N,5,5-trimethyl-1,2,3,4-tetrahydro-5H-<1>benzopyrano<4,3-c>pyridine-2-acetamide
            (3b), and the corresponding acetylurea, 7b.In a battery of seven CNS tests, 7b is one of the most potent cannabinoids so far
            reported.
 CNR:
            5775668

 Author:
            Dell, H.-D.; Kamp, R.; Brons, B.; Schoellnhammer, G.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., GE, 33, 12, 1983, 1633-1637
 Title:
            Pharmacokinetics of Tienocarbine in Rats
 Abstract:
            1,9-Dimethyl-7,8,9,10-tetrahydrothieno<3,2-e>pyrido<4,3-b>indole
            lactate (tienocarbine) 1, is absorbed and distributed very fast after a
            single oral or i.v. dose in rats.Half-lives (b-phase) (i.v./p.o.) 1.9 and 2.2
            h, respectively, VD 6.1/6.4 l/kg, oral bioavailability approx.
            50percent.After dosage for 28 days (2.5 mg/kg/d) all organs
            investigated contained tienocarbine, the N-desmethyl derivate was
            also found in lung and kidneys. 3 days after the last dose no 1 could be
            found in any organ.The quotient brain/blood is approx. 31 after single
            or repeated doses.With these low values of VD, the high brain/blood
            ratio and the constancy of these values tienocarbine differs from many
            other CNS active substances. 1 is intensively metabolised in rats;
            unchanged substance was found neither in urine nor in feces.Besides
            the N-desmethyl derivative, several as yet not identified metabolites
            occur. - Key words: Tienocarbine, bioavailability, N-desmethyl
            derivative, pharmacokinetics
 CNR:
            5792881

 Author:
            Pittner, H.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., GE, 33, 1a, 1983, 13-25
 Title:
            Pharmacodynamic Actions of Celiprolol, a Cardioselective b-Receptor Blocker
 Abstract:
            Pharmacodynamic actions of
            3-<3-acetyl-4-(3-tert-butyl-amino-2-hydroxy-propoxy)-phenyl>-1,1-diethylurea-hydrochloride
            (celiprolol-HCl, in the following briefly called celiprolol; ST 1396-HCl) have been
            investigated in isolated organ preparations, whole animal experiments and biochemical
            trials.Celiprolol is an effective b-adrenergic blocking agent, the pA2 value on the electrically
            stimulated guinea-pig atrium being as great as 8.05.The oral efficacy of this substance has
            been demonstrated by the influence on the isoprenaline-induced tachycardia in conscious
            dogs.In vitro celiprolol blocks the cardiac b-receptors at approximately 20 times lower
            concentrations than the tracheal b-receptors, thus showing relative cardioselectivity.A
            certain degree of ISA (= Intrinsic Sympathetic Activity) is shown by this substance.Celiprolol
            has neither cardiodepressant nor local anesthetic effects over a large concentration
            range.When given in high doses, celiprolol acts as a hypotensive agent in spontaneously
            hypertensive rats and protects laboratory animals from the arrhythmogenic actions of
            k-strophanthoside or aconitine.Celiprolol is devoid of any undesirable effects on liver,
            intestine, kidney or CNS functions even when very high doses are administered. - Key
            words: b-Blockers; Celiprolol, cardioselectivity, pharmacodynamics; ST 1396-HCl
 CNR:
            5793045

 Author:
            Dunky, A.; Mattern, H.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 33, 4a, 1983, 636-640
 Title:
            European Double-Blind Multicenter Study Comparing Meclofenamate
            Sodium and Indometacin in the Treatment of Rheumatoid Arthritis
 Abstract:
            A total of 187 patients with classical or definite rheumatoid arthritis
            (RA) were treated in this double-blind multicenter study in Europe. 94
            patients received 300 mg N-(2,6-dichloro-m-tolyl)anthranilic acid,
            sodium salt (meclofenamate sodium, Meclomen) per day and 93
            patients received 150 mg indometacin per day for 8 weeks after a
            baseline period of two weeks on acetylsalicylic acid.Measures of
            efficacy were an articular index (pain on pressure), an index of
            swelling, duration of morning stiffness, the Functional Test according
            to Keitel, assessments of the patient's condition by both the physician
            and the patient and a comparative assessment of the patient's
            condition made by the physician at the end of treatment.The mean
            values for all efficacy measures indicated continuous improvement in
            both treatment groups throughout the study.At the end of treatment a
            statistically significant improvement was noted within both treatment
            groups (p < 0.001 for all measures) but no significant difference
            between groups, suggesting comparable efficacy.A similar
            improvement was noted on the patient's condition as assessed by both
            the physician and the patient.At the end of treatment 67percent of the
            meclofenamate sodium patients and 63.7percent of the patients
            receiving indometacin were rated as improved by the
            physician.Adverse reactions were reported by distinctly less patients in
            the meclofenamate sodium group (38.8percent) than in the
            indometacin group (51.6percent).There was a statistically significantly
            lower incidence of gastrointestinal adverse reactions other than
            diarrhea in the meclofenamate sodium group than in the indometacin
            group (p < 0.02).Diarrhea had 8 patients (8.5percent) in the
            meclofenamate sodium group and 4 patients (4.3percent) in the
            indometacin group.There were also significantly less CNS-complaints
            in the meclofenamate sodium group than in the indometacin group (p
            < 0.01).This indicates better tolerance with meclofenamate
            sodium.The results of this European double-blind multicenter study
            provide convincing evidence that meclofenamate sodium in a daily
            dose of 300 mg is equally effective to indometacin at a daily dose of
            150 mg in the treatment of symptoms of RA and that meclofenamate
            sodium demonstrates better patient tolerance than indometacin. - Key
            words: Anti-inflammatory drugs, non-steroidal; Indometacin, clinical
            studies; Meclofenamate sodium, clinical studies; Meclomen;
            Rheumatoid arthritis
 CNR:
            5794279

 Author:
            Jahn, U.; Adrian, R. W.; Ismail, S.; Michos, N.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 33, 5, 1983, 726-739
 Title:
            Pharmacological and Toxicological Studies of Binodaline
            Hydrochloride
 Abstract:
            It has been shown, in extensive animal experiments, that
            1-(w-dimethylaminoethylmethyl)-amino-3-phenylindole hydrochloride
            (binodaline HCl, Sgd-Scha 1059), can be regarded as an
            antidepressant with novel characteristics.With anticholinergic and
            histamine-antagonistic effects almost completely lacking, the main
            effects of binodaline HCl are to increase noradrenergic influences and
            to produce CNS depression.The acute toxicity of binodaline HCl is
            comparatively low, and the good tolerance has been demonstrated in
            long-term studies in laboratory animals. - Key words: Antidepressants;
            Binodaline, pharmacology, toxicology; Sgd-Scha 1059
 CNR:
            5794340

 Author:
            Graziani, G.; Cazzulani, P.; Luca, C.; Nava, G.; Testa, R.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 33, 8, 1983, 1161-1168
 Title:
            Denzimol, a New Anticonvulsant Drug. II. General pharmacological
            activities
 Abstract:
            The paper reports on the pharmacological properties of
            N-<b-<4-(b-phenylethyl)phenyl>-b-hydroxyethyl>imidazole
            hydrochloride (denzimol, Rec 15-1533), a compound endowed with
            anticonvulsant properties, and its possible side effects.Effects on the
            CNS, effects on vigilance and general motility are similar to those of
            phenytoin and occur at doses much above anticonvulsant levels.The
            drug has good in vitro antihistamine, anticholinergic and anti-5-HT
            activity which accounts for the effects on the gastrointestinal system
            e.g. inhibition of gastric secretion and motility and anti-ulcer
            properties.There was no significant effect on the cardiovascular system
            or respiration, except an interesting antiarrhythmic activity. - Key
            words: Anticonvulsant drugs; Denzimol, pharmacology; Rec 15-1533
 CNR:
            5794432

 Author:
            Bergey, J. L.; Sulkowski, T.; Much, D. R.; Wendt, R. L.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 33, 9, 1983, 1258-1268
 Title:
            Antiarrhythmic, Hemodynamic and Cardiac Electrophysiological
            Evaluation of
            N-(2,6-Dimethylphenyl)-N'-<3-(1-methylethylamino)-propyl>urea
            (Wy-42,362)
 Abstract:
            The antiarrhythmic, hemodynamic and cardiac electrophysiological
            effects of (Wy-42,362, in the following briefly called Wy)
            N-(2,6-dimethylphenyl)-N'-<3-(1-methylethylamino)propyl>urea were
            examined in several experimental preparations.Wy is an effective
            antiarrhythmic agent when administered i.v. or p.o. in various models
            of canine cardiac arrhythmia.Wy elevated ventricular fibrillatory
            threshold voltage and reverted ouabain-induced, 24- and 48-h post
            coronary artery ligation-induced Jentricular arrhythmias, 37nd
            aconitine-induced atrial arrhythmias at i.v. doses of 4- 15 mg/kg.Wy
            lacked anticholinergic or CNS-stimulant activity.In closed-chest
            anesthetized dogs, Wy at 15 or 25 mg/kg i.v. decreased cardiac output
            (CO).Unlike disopyramide, i.v.Wy did not produce greater reductions in
            CO in anesthetized dogs subjected to previous infarction (72-96 h) as
            compared to normal intact dogs.Wy at 10 or 15 mg/kg i.v. produced
            slight to moderate decreases in contractile force and showed a
            tendency to reduce heart rate and blood pressure.Wy produced a
            generalized depression of cardiac impulse conduction in open-chest,
            pentobarbital anesthetized dogs but conscious dogs exhibited
            relatively little ECG evidence of such depression following double the
            therapeutic i.v. dose.In isolated canine cardiac Purkinje fibers bathed
            in normal K(+)-containing physiological solutions, Wy (1-2E-5 mol/l)
            produced significant reductions in action potential duration while 2E-5
            mol/l also reduced V max and shifted membrane responsiveness
            curves to the right suggesting depressant action on fast Na(+) channel
            conductance.The data indicate that Wy is an effective antiarrhythmic
            agent presumably with a class I mechanism of action. - Key words:
            Antiarrhythmics;
            N-(2,6-Dimethylphenyl)-N'-<3-(1-methylethylamino)propyl>urea,
            pharmacology; Wy-42,362
 CNR:
            5795192

 Author:
            Awouters, F. H. L.; Niemegeers, C. J. E.; Janssen, P. A. J.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 33, 3, 1983, 381-388
 Title:
            Pharmacology of the Specific Histamine H1-Antagonist Astemizole
 Abstract:
            1-(4-Fluorophenylmethyl)-N-<1-(2-(4-methoxyphenyl)-ethyl)-4-pipiridinyl>-1H-benzimidazol-2-amine
            (astemizole) is a chemically novel histamine H1-antagonist.Protection from mast-cell mediated
            shock in rats was obtained with low doses of astemizole.In this model orally administered
            astemizole was more potent and longer acting than any other antihistamine.In studies on
            antihistamine and antiallergic properties of astemizole in mice, rats, guinea-pigs and dogs the
            antiallergic activity appeared to result from a potent and persistent blockade of histamine
            H1-receptors without significant contribution from serotonin antagonism or mast cell protection.On
            isolated tissues and in receptor binding astemizole was selective for histamine H1-antagonism and
            was resistant to routine wash-out.Studies in rats, on isolated tissues and receptor preparations allow
            to conclude that astemizole is a very specific histamine H1 antagonist devoid of serotonin
            antagonism, anticholinergic properties, antagonism of dopamine, other catecholamines, calcium
            and prostaglandins and of a series of non-specific activities, which have been found associated with
            the antihistamine activity in some of the known compounds of this class.Astemizole at very high
            doses neither acted directly on the CNS nor interacted with ethanol, methohexital, chlordiazepoxide,
            haloperidol, fentanyl and tranylcypromine.In contrast to ketotifen, diphenhydramine,
            chlorpheniramine and mepyramine, astemizole did not change the EEG pattern in dogs.In
            laboratory animals astemizole appeared to be very safe upon single and repeated
            administration.There was no evidence for adverse effects on fertility and astemizole was devoid of
            embryotoxic, teratogenic, carcinogenic and mutagenic effects in widely varying test conditions. - Key
            words: Astemizole, pharmacology, review of results; H1-Antihistamines
 CNR:
            5795279

 Author:
            Majchrzak, Michal W.; Kotelko, Antoni; Guryn, Roman; Lambert,
            Joseph B.; Szadowska, Anna; Kowalczyk, Kazimierz
 Reference:
            Journal, JPMSAE, J.Pharm.Sci., EN, 72, 3, 1983, 304-306
 Title:
            Synthesis and Action on the Central Nervous System of Mescaline
            Analogues Containing Piperazine or Homopiperazine Rings
 Abstract:
            Structural juxtaposition of the 3,4,5-trimethoxyphenyl group in the
            same molecule with a piperazine or homopiperazine ring has been
            realized in a series of mescaline analogues (I-IV) as part of an
            investigation into the the pharmacological properties of the
            seven-membered perhydro-1,4-diazepines (homopiperazines).The
            analogous six-membered piperazines were synthesized and tested as
            reference substances to determine whether the seven-membered ring
            conveyed special properties.A variety of pharmacological tests of
            action on the CNS showed that replacement of the amino group in
            mescaline by the heterocycles significantly alters the biological
            activity.In particular, both the piperazine and the homopiperazine
            derivatives displayed sedative activity to about the same extent.
 CNR:
            5836006

 Author:
            Kar, A.
 Reference:
            Journal, JPMSAE, J.Pharm.Sci., EN, 72, 9, 1983, 1082-1084
 Title:
            Cinchophen Analogues as Potential CNS Agents
 Abstract:
            Several amides of cinchophen were prepared and evaluated as CNS
            agents.Compounds III, VII, XII, XIII, and XIV exhibited analgesic
            activity while I, III, and XIV acted as CNS depressants.
 CNR:
            5868657

 Author:
            Cafaggi, S.; Romussi, G.; Ciarallo, G.; Bignardi, G.
 Reference:
            Journal, FRPSAX, Farmaco Ed.Sci., EN, 38, 10, 1983, 775-783
 Title:
            CYCLOADDITION OF DICHLOROKETENE TO N,N-DISUBSTITUTED
            3-AMINOMETHYLENE-5-HYDROXY-2,2-DIMETHYL-7-PENTYL-4-CHROMANONE:
            SYNTHESIS OF 2H,5H-PYRANO<3,2-c><1>BENZOPYRAN DERIVATIVES
 Abstract:
            The synthesis of N,N-disubstituted
            3-aminomethylene-5-hydroxy-2,2-dimethyl-7-pentyl-4-chromanones (III) and their reaction with
            dichloroketene are described.The resulting cycloadducts (IV) gave, by dehydrochlorination, the
            N,N-disubstituted
            4-amino-3-chloro-10-hydroxy-5,5-dimethyl-8-pentyl-2H,5H-pyrano<3,2-c><1>benzopyran-2-ones
            (V), which are structurally related to tetrahydrocannabinols.Only the compound (Va) displayed a
            very weak stimulant activity on the CNS.
 CNR:
            5875184

 Author:
            Roma, G.; Balbi, A.; Ermili, A.; Vigevani, E.
 Reference:
            Journal, FRPSAX, Farmaco Ed.Sci., IT, 38, 8, 1983, 546-558
 Title:
            RICHERCHE SU 1,5-BENZODIAZEPINE. Nota V. - Sintesi di derivati della
            pirazol<3,4-b><1,5>benzodiazepine e della 5H-pirimido<4,5-b><1,5>benzodiazepina
 Abstract:
            The reaction of 4-(alkylamino)-1,3-dihydro-2H-1,5-benzodiazepin-2-ones (Ia-c) with
            N,N-dimethylformamide in the presence of phosphorus pentachloride at room temperature
            gave rise to the formation of
            4-(dialkylamino)-3-<(dimethylamino)methylene>-1,3-dihydro-2H-1,5-benzodiazepin-2-ones
            (IXa-c) which were useful starting materials to achive the synthesis of tricyclic
            1,5-benzodiazepine derivatives.Actually (IXa), selected for the smallest steric hindrance of
            the 4-dialkylamino substituent, by reaction with hydrazines afforded
            pyrazolo<3,4-b><1,5>benzodiazepine derivatives reaction with guanidine or amidines gave
            percentH-pyrimido<4,5-b><1,5>benzodiazepine derivatives.The structures of isomeric
            N-methylpyrazoles (Xc) and (XIa) and of N-phenylpyrazole (Xb) were elucidated by
            comparison with compounds prepared by unequivocal chemical methods.Pharmacological
            evaluation of some of the products showed only generic CNS depressant activity.
 CNR:
            5876396

 Author:
            Kanekar, D. S.; Deodhar, K. D.; Prabhu, A. V.
 Reference:
            Journal, JICSAH, J.Indian Chem.Soc., EN, 60, 1983, 877-881
 Title:
            N,N-Disubstituted-b-Methyl-p-Methoxy Cinnamamides, as Possible
            CNS Depressants
 Abstract:
            In view of the expected ease of decarboxylation of
            b-(4-methoxyphenyl)glutaconic anhydride in basic condition with
            secondary amines, it was realised that they could be converted into
            b-methyl substituted cinnamamide in one step reaction.These
            compounds showed mild CNS depressant action.
 CNR:
            5916092

 Author:
            Joshi, Krishna C.; Pathak, Vijai N.; Garg, Urmila
 Reference:
            Journal, JICSAH, J.Indian Chem.Soc., EN, 60, 1983, 1074-1076
 Title:
            Synthesis and CNS Activity of Some Fluorine Containing
            Pyrazolo<5,1-c><1,2,4>Triazines
 Abstract:
            Seven new fluorinated pyrazolo<5,1-c><1,2,4>triazines have been
            synthesized by the condensation of pyrazole diazonium salt with
            1,3-diketones in aqueous buffered solution.An intermediate is
            obtained, which on thermal cyclization in glacial acetic acid, gave
            pyrazolo<5,1-c><1,2,4>triazines.These compounds have been
            characterized by ir, pmr, and 19F-nmr spectral studies.Most of the
            compounds display significant anti-inflammatory activity.
 CNR:
            5916443

 Author:
            Joshi, Krishna C.; Dubey, Kalpana; Dandia, Anshu
 Reference:
            Journal, JICSAH, J.Indian Chem.Soc., EN, 60, 1983, 369-372
 Title:
            Possible Psychopharmacological Agents. Part-XIII: Synthesis and
            CNS Activity of Some New Fluorine Containing 1,2,4-Triazine
            Derivatives
 Abstract:
            CNS activity of some new fluorinated phenylglyoxals and
            5-(fluorophenyl)-3-mercapto-1,2,4-triazines has been evaluated and
            the compounds are found to be CNS depressants.In addition, a
            number of new fluorine containing
            3-substituted-5-(fluorophenyl)-1,2,4-triazine derivatives of
            pharmacological interest have been synthesized by the treatment of
            3-mercapto-1,2,4,-triazine with appropriate
            dialkylaminoethylchloridehydrochloride, fluorophenacyl chloride and
            halogenated acids.These compounds have also been screened for
            priliminary CNS activity and one of them is found to act as a stimulant
            and to induce convulsions while the rest are CNS depressants.All
            synthesized compounds have been characterized by their m.p.s.
            elemental analyses, tlc, ir and 1H nmr.
 CNR:
            5919624

 Author:
            Press, Jeffery B.; Hofmann, Corris M.; Wiegand, Gretchen E.; Safir,
            Sidney R.
 Reference:
            Journal, JHTCAD, J.Heterocycl.Chem., EN, 19, 1982, 391-394
 Title:
            Thiophene Systems. 7. Pyrido<3,2-b>thieno<3,4-e><1,4>diazepine
            Derivatives with Potential CNS Activity (1,2)
 Abstract:
            Pyrido<3,2-b>thieno<3,4-e><1,4>diazepines (1a-d) were synthesized
            to investigate their potential CNS activity.Synthesis of the desired ring
            system was effected by condensation of 2,3-diaminopyridine (3) with
            methyl tetrahydro-4-oxo-3-thiophenecarboxylate (4).Structural
            assignment of the major condensation product 5 was determined by
            comparison of 1H nmr absorptions of 5 with those of related methyl
            lactam derivatives 11 and 14.A discussion of the possible mechanism
            leading to 5 in preference to isomeric lactam 6 is presented.Biological
            evaluation of 1a-d revealed no interesting properties.
 CNR:
            5564402

 Author:
            Hirai, Kentaro; Sugimoto, Hirohiko; Ishiba, Teruyuki; Fujishita, Toshio;
            Tsukinoki, Yuji; Hirose, Katsumi
 Reference:
            Journal, JHTCAD, J.Heterocycl.Chem., EN, 19, 1982, 1363-1369
 Title:
            Synthesis and Biological Activity of
            (3,5-Disubstituted-1H-1,2,4-triazol-1-yl)benzophenone Derivatives
 Abstract:
            The synthesis of
            (5-acylaminomethyl-3-carbamoyl-1H-1,2,4-triazol-1-yl)benzophenone
            derivatives 4a-i, 14a-d, 15a-d, 16a-c, is described.Acylation of the key
            intermediate, 1-benzoylphenylazo-1-aminoacetamide 7, followed by
            cyclization in the presence of acid afforded 1H-1,2,4-triazole
            derivatives.These compounds were evaluated for their central nervous
            system (CNS) activity.Some of these compounds exhibited high
            activities in anti-pentylen tetrazole and rotarod test in mice when orally
            administered.
 CNR:
            5566717

 Author:
            Agarwal, Shiv K.; Saxena, Anil K.; Jain, Padam C.; Anand, Nitya
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 21, 10, 1982, 914-918
 Title:
            Synthesis and Structure Activity Relationship in 1-(Substituted
            aminophenoxy)-3-<N1-(N4-arylpiperazinyl)>propanes
 Abstract:
            1-(Aminophenoxy)-3-<N1-(N4-arylpiperazinyl)>propanes (1-8) have been
            prepared by the catalytic hydrogenation of
            1-(nitrophenoxy)-3-<N1-(N4-arylpiperazinyl)>propanes.The reaction of
            aminophenoxypiperazinylpropanes (1-8) with acetic anhydride gives the
            corresponding
            1-(acetamidophenoxy)-3-<N1-(N4-arylpiperazinyl)>propanes (9-15) and
            with methanesulphonyl chloride the corresponding
            1-(methanesulfonamidophenoxy)-3-<N1-(N4-arylpiperazinyl)>propanes
            (16-19) are obtained.The amino compounds (3 and 4) on treatment with
            lactim thioethers and isocyanates/isothiocanates afford the
            corresponding 1-<(heterocyclylamino)phenoxy>- (20-30) and
            1-(ureido/thioureidophenoxy)-3-<N1-(N44-arylpiperazinyl)>propanes
            (31-37).Some of these compunds show potent CNS depressant,
            hypotensive, a-adrenoceptor blocking, antiinflammatory and diuretic
            activities.Among these compounds
            1-(4-aminophenoxy)-3-<N1-(N4-(2-methoxyphenyl)piperazinyl)>propane
            (4) is found to be potent neuroleptic.
 CNR:
            5573996

 Author:
            Tandon, Renu; Jain, G. K.; Khanna, N. M.
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 21, 3, 1982, 265-266
 Title:
            Ecdysterone from Forrestia mollissima Blume
 Abstract:
            n-Butanol extract of the whole plant of Forrestia mollissima Blume
            yields ecdysterone (I), which shows marginal CNS depressant activity.
 CNR:
            5575121

 Author:
            Shukla, J. S.; Rastogi, Renu
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 21, 4, 1982, 375-377
 Title:
            Synthesis of
            2-<p-(Arylideneamino)phenyl>-3-<3/4-(2-phenylimino-4-oxo-2,3,4,5-tetrahydrothiazol-3-yl)phenyl>quinazolin-4-ones
            as CNS Agents
 Abstract:
            A series of 2-<p-(arylideneamino)phenyl>-3-arylquinazolin-4-ones (6-29) and
            2-<p-(arylideneamino)phenyl>-3-<3/4-(2-phenylimino-4-oxo-2,3,4,5-tetrahydrothiazol-3-yl)phenyl>quinazolin-4-ones
            (30-35) have been prepared.The pharmacological screening results show that these compounds exhibit CNS
            depressant and anticonvulsant activities.
 CNR:
            5576408

 Author:
            Tripathi, Shephali; Ahmad, Shakeel; Barthwal, J. P.; Kishor, K.; Tangri,
            K. K.; Bhargava, K. P.
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 21, 4, 1982, 379-380
 Title:
            Synthesis and CNS Activity of 2-(N-Arylaminoacetylmercapto)- and
            2-(N-Arylacetamidomercapto)-benzimidazoles
 Abstract:
            The title mercaptobenzimidazoles (1a-t) have been synthesised and
            screened for their anticonvulsant and monoamine oxidase (MAO)
            inhibitory activities.Some of the compounds provide 80percent
            protection against pentylenetetrazole-induced convulsions and
            maximal electroshock-induced convulsions.Most of the compounds
            exhibit promising MAO activity at final concentrations of 5 x 10-4 M and
            2.5 x 10-4 M and are nontoxic (ALD50 = 1080 mg/kg i. p.).
 CNR:
            5576410

 Author:
            Agarwal, Shiv K.; Kumar, Yatendra; Saxena, Anil K.; Jain, Padam C.;
            Anand, Nitya
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 21, 5, 1982, 435-439
 Title:
            Synthesis and Biological Activities of 3-Substituted
            1-Aryloxyaminopropanes
 Abstract:
            A number of 3-substituted 1-aryloxyaminopropanes (9-43) have been
            prepared by the reaction of appropriate hydroxyaryl compound with
            1-chloro-3-<N1-(N4-aryl-piperazinyl/piperidinyl)>propanes (1-8).The
            1-(6/7-quinolyloxy)-3-substituted-aminopropanes (46-49) are obtained
            by condensation of 6/7-hydroxyquinoline with
            1-bromo-3-chloropropane and subsequent treatment of
            quinolyloxy-chloropropanes (44-45) thus obtained with appropriate
            amines. 1-(6/7-Quinolyloxy)-3-substituted-propan-2-ols (52-53) are
            synthesized by the reaction of 6/7-hydroxyquinoline with
            epichlorohydrin followed by opening of epoxides (50,51) with suitable
            amines.Some of these compounds have shown potent CNS
            depressant, hypotensive, a-adrenoceptor blocking, antiinflammatory
            and diuretic activities.
 CNR:
            5576430

 Author:
            Varma, Rajendra S.; Pandey, Rajnish K.
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 21, 2, 1982, 157-159
 Title:
            Synthesis of 5-Methyl-3-arylthiosemicarbazono-2-indolinones and
            Their 1-Aminomethyl Derivatives as Potential Biologically Active
            Agents
 Abstract:
            5-Methylisatin undergoes condensation with various p-substituted
            arylthiosemicarbazides to give
            5-methyl-3-arylthiosemicarbazono-2-indolinones (Ia-e).A similar
            condensation of 1,5-dimethylisatin with p-substituted
            arylthiosemicarbazides gives
            1,5-dimethyl-3-arylthiosemicarbazono-2-indolinones (IIa-e).Mannich
            reaction on I using morpholine and piperidine gives
            5-methyl-1-morpholinomethyl- and
            5-methyl-1-piperidinomethyl-3-arylthiosemicarbazone-2-indolinones
            (IV and V), respectively.These indolinones have been screened for
            their CNS and antibacterial activities.Attempts have been made to
            establish SAR.
 CNR:
            5576771

 Author:
            Agarwal, Rajesh; Chaudhary, Chapla; Misra, V. S.
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 21, 12, 1982, 1110-1113
 Title:
            Synthesis and CNS Activity of 4-Arylideneamino-N,N-diphenylbenzamides,
            1-<p-(N,N-Diphenylcarbamoyl)phenyl>-3-(p-substituted phenyl)thioureas and
            6-Substituted
            3-<N-(3H-2-Methyl-4-oxo-3-quinazolylamino)methyl>2-oxo/thio-benzoxazoles
 Abstract:
            4-Arylideneamino-N,N-diphenylbenzamides (IIIa-h),
            1-<p-(N,N-diphenylcarbamoyl)phenyl>-3-(p-substituted phenyl)thioureas (IVa-d)
            and 6-substituted
            3-<N-(3H-2-methyl-4-oxo-3-quinazolylamino)methyl>-2-oxo-/thio-benzoxazoles
            (Va-d) have been synthesized from 4-amino-N,N-diphenylbenzamide
            (IIa).Similarly thioureas IVe-h and benzoxazoles Ve-h have been prepared from
            2-aminoquinazolin-4(3H)-one (IIb).Compounds III, IV and V are found to be
            psychotropic and nontoxic.
 CNR:
            5577480

 Author:
            Ong, Helen H.; Profitt, James A.; Anderson, V.B.; Spaulding, Theodore
            C.; Wilker, Jeffrey C.; et al.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 25, 10, 1982, 1150-1153
 Title:
            Tricyclics with Analgesic and Antidepressant Activity. 2.
            <<(Alkylamino)ethyl>thio>dibenzo<b,f>thiepins and 10,11-Dihydro
            Derivatives
 Abstract:
            A series of <<<(alkylamino)ethyl>thio>dibenz<b,f>thiepins (III) and their
            10,11-dihydro derivatives (IV) was synthesized and subjected to broad
            analgesic/CNS screening.Preliminary results indicated a combination
            of analgesic/antidepressant profiles, similar to that observed for the
            <<(alkylamino)ethyl>thio>dibenz<b,f>oxepins (I) and their
            corresponding dihydro derivatives (II).The most active congener from
            the present series, 10b, shows an antinociceptive potency in the
            pentazocine range as assessed by phenyl-p-quinone-induced writhing
            (PQW) and tail flick in mice.It is also more than twice as active as
            imipramine in preventing tetrabenazine-induced ptosis (TBZ), a test
            widely recognized to be of predictive value for clinically efficacious
            antidepressants.
 CNR:
            5640229

 Author:
            Hirai, Kentaro; Fujishita, Toshio; Ishiba, Teruyuki; Sugimoto, Hirohiko; Matsutani,
            Shigeru; at al.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 25, 12, 1982, 1466-1473
 Title:
            Amino Acid Amide Derivatives of
            2-<3-(Aminomethyl)-4H-1,2,4-triazol-4-yl>benzophenones, a Novel Class of Annelated
            Peptidoaminobenzophenones
 Abstract:
            A series of the title compounds was prepared via condensation of the
            3-(aminomethyl)triazolylbenzophenone (5) with N-protected amino acids, followed by
            deprotection, amination of the 3-<(chloroacetamido)methyl>triazolylbenzophenone
            (6a,b), or reduction of the relevant azide derivative (6c).Some of the title compounds
            were also derived directly from the quinazolines 3 or 4 by acid-induced rearrangement,
            followed by deprotection.These new amino acid amide derivatives of the
            triazolylbenzophenones (2) were evaluated for central nervous system (CNS)
            activity.Members of this class of compounds exhibited a high level of CNS activities.For
            example,
            2',5-dichloro-2-<3-<(glycylamino)methyl>-5-methyl-4H-1,2,4-triazol-4-yl>benzophenone
            (2c) was as active as triazolam, with an ED50 of 0.58 mg/kg (mice, po), against
            antifighting activity in the foot shock-induced fighting test.Other triazolylbenzophenone
            derivatives (2a-f) showed similar pharmacological activities.
 CNR:
            5640329

 Author:
            Verma, Rajendra S.; Pandey, Rajnish K.; Kumar, Piyush
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 21, 1982, 775-777
 Title:
            Synthesis of Alkyl 4-<<4'-(1,2-Dihydro-5-chloro-2-oxo-3H-indol-3-ylideneamino)-benzoyl>amino>benzoates and Related
            Compounds
 Abstract:
            The condensation of various 4-<(4'-aminobenzoyl)amino>-benzoates (II) with 5-chloroisatin results in the formation of
            alkyl 4-<<4'-(1,2-dihydro-5-chloro-2-oxo-3H-indol-3-ylideneamino)-benzoyl>amino>benzoates (V).Similar condensation
            of II with 5-chloro-1-methylisatin yields alkyl
            4-<<4'-(1,2-dihydro-1-methyl-5-chloro-2-oxo-3H-indol-3-ylideneamino)benzoyl>amino>benzoates (VI).The Mannich
            reaction on V using morpholine and piperidine as secondary amines furnishes alkyl
            4-<<4'-(1,2-dihydro-1-morpholine/piperidinomethyl-5-chloro-2-oxo-3H-indol-3-ylideneamino)-benzoyl>amino>benzoates
            (VII).Copounds (V-VII) have been screened for their CNS and antitubercular activity against Mycobacterium tuberculosis
            H37Rv.
 CNR:
            5643372

 Author:
            Srivastava, Neera; Gupta, Anurag Ateet; Gupta, Anil K. Sen
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 21, 1982, 787-789
 Title:
            Studies on Potential Indole Derivatives: Part III-Synthesis and CNS Activity of Some New
            1-Substituted-aminomethyl-3-<p-(N,N-diethylcarbamoyl)phenylimino>-5-substituted-indolin-2-ones
 Abstract:
            5-Substituted-indolin-2, 3-diones (1-3) undergo condensation with p-(N,N-diethylcarbamoyl)aniline
            (4) to give the respective 3-<p-(N,N-diethylcarbamoyl)phenylimino>-5-substituted-indolin-2-ones
            (5-7), which on Mannich reaction with different amines furnish 1-substituted-aminomethyl-3-<p-(N,
            N-diethylcarbamoyl)phenylimino>-5-substituted-indolin-2-ones (8-22).These compounds have
            been found to be non-toxic and CNS active agents.
 CNR:
            5643377

 Author:
            Gupta, Anil K. Sen; Srivastava, Neera; Gupta, Anurag A.
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 21, 8, 1982, 793-795
 Title:
            Synthesis of 2-Alkyl-3-substituted-indoles as Potential Biodynamic
            Agents
 Abstract:
            A series of 2-methyl-3-(3-substituted-2-thioxo-5-oxadiazolylmethyl)
            indoles (6-15) and 2-n-propyl-3-(N-substituted-acetamido)-indoles
            (16-25) have been synthesised evaluated for their antimicrobial and
            CNS activities.
 CNR:
            5643379

 Author:
            Ribalta, Miguel; Ribas, Maria; Tobed, Antonio Martinez; Basi, Nuria;
            Zapatero, Jorge; Bruseghini, Leonida
 Reference:
            Journal, EJMCA5, Eur.J.Med.Chem.Chim.Ther., EN, 17, 2, 1982,
            187-190
 Title:
            Synthesis and pharmacological properties of
            2,4,6,8-tetraphenylbispidin-9-ones
 Abstract:
            A series of 2,4,6,8-tetraphenyl-3,7-diazabicyclo
            <3.3.1.>nonan-9-oneureas and thioureas was prepared by treatment of
            the corresponding bispidinones with isocyanates or
            isothiocyanates.These compounds were screened for their activities
            on CNS and for their antiulcer activity.Several compounds showed a
            weak activity in the pharmacological tests, but one of them was
            sufficient to justify further development.Key-words: Bispidinones. -
            Urea deriv. - Thiourea deriv. - Antiulcer activity. - CNS activity.
 CNR:
            5677990

 Author:
            Kumar, Naresh; Dhaon, Madhup K.; Agarwal, Shiv K.; Saxena, Anil K.; Jain, Padam C.; et al.
 Reference:
            Journal, EJMCA5, Eur.J.Med.Chem.Chim.Ther., EN, 17, 4, 1982, 312-316
 Title:
            Agents acting on CNS. Part XXIX Synthesis of seco-analogs of centbutindole, a potent
            neuroleptic (1)
 Abstract:
            In order to study the role of molecular rigidity for the neuroleptic activity of
            2-g-(p-fluorobenzoyl)propyl-1,2,3,4,6,7,12,12a-octahydropyrazino<2',1':6,1>pyrido<3,4-b>indole
            1a, its four seco analogs indolylmethylpiperazine 5, amino-ethylpyridoindole 15,
            aminomethylpyridoindole 23 and indolodiazocine 28 have been synthesized and evaluated for
            neruoleptic activity.These compounds showed weaker neuroleptic activity as compared to 1a,
            suggesting that both tryptamine and piperazine moietie; in a rigid conformation are essential for
            this activity.Key-words : Pyrazinopyridoindole derivatives. - Centbutindole. - Indile derivatives.-
            Neuroleptics. - CNS (activity).
 CNR:
            5680234

 Author:
            Okafor, C. O.; Steenberg, M. L.; Buckley, J. P.
 Reference:
            Journal, CPBTAL, Chem.Pharm.Bull., EN, 30, 1, 1982, 302-318
 Title:
            Studies in the Heterocyclic Series. XVI. Open Azaphenothiazines as
            New Central Nervous System Depressants
 Abstract:
            Acid-catalyzed condensation of 2-amino-3-mercapto-6-methylpyridine
            and 3-aminopyridine-2<1H>-thiones with 4-chloropyrimidines having
            free 5-carbon centers gave
            N-(3-mercapto-2-pyridyl)-6-pyrimidinylamines and
            N-(2-thioxo-3-pyridyl)-6-pyrimidinylamines, which we have described
            as open 1,3,9-triaza- and 1,3,6-triaza-phenothiazines, respectively.A
            newly developed method of reducing nitro groups was used for
            preparing the aminopyridine precursors.Eight new and five related
            compounds including an open 1,9-diazaphenoxazine were tested in
            rats and mice and found to display central nervous
            system(CNS)-depressant activities.The most active compound in the
            series is
            N-(6-chloro-2<1H>-thioxo-3-pyridyl)-2,4-diamino-6-pyrimidinylamine,
            an open 1,3,6-triazaphenothiazine derivative.Structure-activity
            correlations are discussed on the basis of the biological data.
 CNR:
            5683511

 Author:
            Emons, G.; Gruehn-Schultek, K.-M.; Isedor, S.; Ball, P.; Knuppen, R.
 Reference:
            Journal, STEDAM, Steroids, EN, 39, 3, 1982, 291-300
 Title:
            PHARMACOKINETICS OF FREE CATECHOLESTROGENS AND
            CATECHOLESTROGEN BENZOATES
 Abstract:
            To provide a definite basis for studies on the biological effects of
            exogenously administered catecholestrogens, the time courses of the
            concentrations of these estrogens in serum, pituitary and CNS-tissues
            were studied in male rats after s.c. injection of either 150 mg of
            4-hydroxyestradiol or 2-hydroxyestradiol (dissolved in 200 ml sesame
            oil/ethanol/ascorbic acid; 97.5/2.5/0.1; vol/vol/wt) or equimolar
            amounts of 4-hydroxyestradiol 3,4-dibenzoate or 2-hydroxyestradiol
            2,3-dibenzoate (dissolved in 200 ml sesame oil).The injection of free
            catecholestrogens resulted in bolus-like elevations of the serum and
            tissue concentrations of the respective compound (max. values up to 9
            ng/ml, half-life below 1 h) whereas the injection of catecholestrogen
            benzoates gave lower (max. values about 1 ng/ml) but prolonged
            elevations (half-life approx. 24 h and 32 h for 4-OHE2 and 2-OHE2) or
            the respective free catecholestrogen.
 CNR:
            5684385

 Author:
            Tandon, S. K.; Doval, D. C.; Shanker, K.; Sinha, J. N.
 Reference:
            Journal, PHARAT, Pharmazie, EN, 37, 5, 1982, 388-389
 Title:
            Synthesis and CNS Activity of Newer
            2,5-Disubstituted-1,3,4-oxadiazoles
 Abstract:
 CNR:
            5686354

 Author:
            Husain, M. I.; Singh, Eira
 Reference:
            Journal, PHARAT, Pharmazie, EN, 37, 6, 1982, 408-410
 Title:
            Some New 2-Aryloxymethyl-3-a-substituted
            Carboxymethyl-6,8-substituted-4-quinazolones as Possible
            Anticonvulsants
 Abstract:
            In view of their expected MAO inhibitory, CNS depressant and
            anticonvulsant properties, thirty new 2-aryloxymethyl-3-a-substituted
            carboxymethyl-6,8-substituted-4-quinazolones were synthesized by the
            reaction of substituted anthranil with various amino acids in
            pyridine.Some of these compounds at a concentration of 1*10-3 mol/l
            inhibited rat brain monoamine oxidase (MAO) in vitro and provided
            protection against pentylenetetrazole induced convulsions in mice.
 CNR:
            5686356

 Author:
            Pant, Jyotsna; Pant, K. K.; Gupta, T. K.; Bhargava, K. P.; Joshi, B. C.
 Reference:
            Journal, PHARAT, Pharmazie, EN, 37, 3, 1982, 176-177
 Title:
            Synthesis and Pharmacological Studies of
            2'-Sulfonyl<3-(3H-2,4-disubstituted-1,5-benzodiazepino)>-2,5-dimethyl-6,7-benzomorphans.
 Abstract:
            2'-Sulfonyl<3-(3H-2,4-dimethyl-1,5-benzodiazepino)>-2,5-dimethyl-6,7-benzomorphan (3a),
            2'-sulfonyl<3-(3H-2-methyl-4-phenyl-1,5-benzodiazepino)>-2,5-dimethyl-6,7-benzomorphan
            (3b) and
            2'-sulfonyl<3-(3H-2methyl-4-oxo-5H-1,5-benzodiazepino)>-2,5-dimethyl-6,7-benzomorphan
            (3c), synthesized from 2,5-dimetyl-6,7-benzomorphan (1) in three steps via
            chlorosulfonation, condensation with sodium salt of acetylacetone, benzoylacetone and
            ethyl acetoacetate separately and condensation with o-phenylenediamine, were studied for
            their pharmacological activities.It was found that 3a has mild CNS depressant, analgesic
            and anticonvulsant (against petitmal type of seizures) activities. 3b has significant
            antidepressant and mild analgesic activities while 3c has CNS depressant, mild analgesic
            and anticonvulsant activities (against petitmal type seizures).
 CNR:
            5689432

 Author:
            Lata, A.; Satsangi, R. K.; Srivastava, V. K.; Kishor, K.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 32, 1, 1982, 24-27
 Title:
            Monoamine Oxidase Inhibitory and CNS Activities of some Quinazolinones
 Abstract:
            16 new compounds have been synthesized in the series of
            3-aryl-2-(1'-aryl-piperazin-4'-yl-carboxamidomethyl)-mercapto-quinazolinones.The
            compounds showed interesting results in anticonvulsant, hypnotic and
            monoamine oxidase (MAO) inhibitory screenings and are non-toxic.SAR were
            evaluated.- Keywords: Anticonvulsants; Hypnotics; MAO inhibitors,
            Quinazolinones, CNS activities, MAO inhibition
 CNR:
            5733861

 Author:
            Beitman, R. E.; Kuzma, R. J.; McMahon, F. G.; Morledge, J.; Mroczek,
            W.; et al.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 32, 8a, 1982, 988-993
 Title:
            Comparative Efficacy and Safety of Lofexidine and Clonidine Given
            Alone or Concomitantly with Hydrochlorothiazide in Hypertensive
            Outpatients
 Abstract:
            In order to determine the effective therapeutic dose range of
            2-<1-(2,6-dichlorophenoxy)-ethyl>-2-imidazoline hydrochloride
            (lofexidine, LofetensinR and LoxacorR) and clonidine and to compare
            the efficacy and safety of lofexidine to those of clonidine when either
            drug is given alone or concomitantly with hydrochlorothiazide (HCTZ),
            we conducted a double-blind parallel study of lofexidine and clonidine
            alone or in combination with HCTZ in patients with mild to moderate
            essential hypertension, who had placebo (baseline) erect diastolic
            blood pressures within the range of 95 - 130 mmHg.This interim report
            involves 112 patients studied at 3 of the 9 investigational sites for
            which the data have been reviewed.Randomization resulted in 54
            patients treated with lofexidine and 58 treated with clonidine.The
            results at the 6 other investigational sites will be reported at a later
            date.The first preliminary results of the subsequent open long-term
            study over a 2-year period with lofexidine as sole treatment or in
            combination with HCTZ are also reported.After determination of
            baseline blood pressure following a 2 - 4 weeks' treatment with
            placebo, patients were treated with increasing doses of lofexidine or
            clonidine.From 0.2 mg b.i.d. upwards HCTZ wasadded at doses of 50 -
            100 mg/day.Upward dose titration continued until diastolic blood
            pressure </= 90 mmHg for 2 consecutive visits or intolerable side
            effects occurred or a maximum dose of 0.8 mg b.i.d. + HCTZ was
            reached.Patients who achieved blood pressure control entered the
            maintenance period of 3 months at their controlling dose.The
            percentages of patients titrated to control of blood pressure with study
            medication alone was greater with clonidine (39percent) than with
            lofexidine (21percent).The percentage of patients who dropped from
            the study with side effects in the clonidine group (29percent) was more
            than double that established for the lofexidine group (13percent).These
            results indicate that the effects of lofexidine are not identical to those of
            clonidine under the conditions of this study.However, with the addition
            of HCTZ (50 - 100 mg/day) to study medication (0.2 mg - 0. 8 mg b.i.d.)
            the percentage of patients titrated to control of blood pressure (drug
            alone and with HCTZ) was similar in the two groups (lofexidine
            79percent, clonidine 72percent).Likewise, the percentages of patients
            who completed the 12-week maintenance period were similar with
            each treatment.Results of clinical laboratory tests, ECG's, chest
            X-rays, and eye examinations revealed no changes attributed to
            treatment with lofexidine and clonidine.Those changes that did occur
            were similar in the 2 treatment groups.The most commonly reported
            adverse effects with lofexidine were dryness (48percent), drowsiness,
            fatigue, or other CNS symptoms (50percent), cardiovascular
            symptoms (26percent) or G.I complaints (31.5percent); these effects
            were reported by similar percentage of clonidine patients.However, the
            percentages of patients who dropped from the study with side effects
            was greater in the ...
 CNR:
            5733907

 Author:
            Morita, T.; Fukuda, T.; Sukamoto, T.; Tajima, S.; Sato, I.; et al.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 32, 9, 1982, 1060-1068
 Title:
            General Pharmacology of KB-944, a New Calcium Antagonist
 Abstract:
            The general pharmacology of diethyl
            4-(benzothiazol-2-yl)benzylphosphonate (KB-944) was studied with the
            following results: 1.Among various phenomena or activities related to
            the CNS, KB-944 (10 - 100 mg/kg p.o.) exerted no significant influence
            on the locomotor activity of mice, or on muscle relaxation, various
            experimental convulsions, barbital anesthesia or on false pain reflex in
            tail pinch test in mice, or on the normal body temperature of rats.The
            drug (0.3 - 3 mg/kg i.v.) did not significantly affect spinal reflex in cats,
            either.However, it (10 - 100 mg/kg p.o.) brought about a strong
            inhibition of acetic acid-induced writhing. 2.Among activities of the
            gastrointestinal system, KB-944 administered at a high dose level
            inhibited small intestinal propulsion in mice (100 mg/kg p.o.), biliary
            secretion in rats (100 mg/kg i.d.), and gastric secretion in rats (30
            mg/kg i.d.).These actions of KB-944 were equivalent in strenght to
            those of diltiazem. 3.Among activities of smooth muscles, KB-944 in
            concentration not less than 1E-7 g/ml reduced the amplitude or
            frequency of spontaneous movement of isolated rabbit ileums and of
            isolated rat uteri.Besides, it caused a non-competitive inhibition of the
            acetylcholine-, histamine- and BaCl2-induced contractions of isolated
            guinea pig ileums (3*E-7 - 1E-6 g/ml) and the
            adrenaline(epinephrine)-induced contraction of isolated guinea pig vas
            deferens (3*E-6 - 1E-5 g/ml).The respective pD'2 values were 5.52,
            5.90, 5.61, and 4.71.These inhibitory actions of KB-944 were
            equivalent to those of diltiazem. 4.The autonomic or the motor nervous
            system was not appreciably affected by KB-944.In effect, the drug
            produced no significant effect on nictitating membrane contraction in
            cats or gastrocnemius muscle contraction in rats due to stimulation of
            the ischiadic nerve, nor did it exert a superficial anesthetic effect in
            guinea pigs (0.125 - 1.0percent) or local irritation in rabbits (0.25 -
            1.0percent). 5.KB-944 inhibited carrageenin-induced rat paw edema
            (100 mg/kg p.o.) and decreased urine volume and urinary electrolyte
            excretion (30 and 100 mg/kg p.o.).On the other hand, it did not change
            partial thromboplastin time (30 and 100 mg/kg p.o.). - Keywords:
            Calcium antagonists; Diethyl 4-(benzothiazol-2-yl)benzylphosphonate,
            general pharmacology; Diltiazem; KB-944; Vasodilators
 CNR:
            5733920

 Author:
            Aschoff, J. C. .; Claus, D.; Hetzel, W. D.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., GE, 32, 3, 1982, 286-289
 Title:
            Tiapride Therapy of centrally Produced Dyskinesia / Examination of
            the serum levels of protein, LH and FSH
 Abstract:
            The effect of
            N-(2-diethylaminoethyl)-2-methoxy-5-(methylsulfonyl)-benzamide
            hydrochloride (tiapride, Tiapridex), a dopamine antagonist, on the
            serum levels of prolactin, luteinising hormone (LH) and follicle
            stimulating hormone (FSH) was studied on 20 healthy individuals and
            10 patients with dyskinesia resulting from extrapyramidal
            disorders.Daily doses of 300 mg in healthy subjects and 300-800 mg
            in patients with dyskinesia resulting from CNS disorders, were found to
            increase serum prolactin levels without causing amenorrhoea or
            galactorrhoea.The drug seemed to have no effect on LH and FSH
            concentrations in the serum. - Key words: Dopamine, antagonists *
            FSH * Gonadotrophic substances * LH * Prolactin * Tiapride, clinical
            pharmacology * Tiapridex
 CNR:
            5734095

 Author:
            Friderichs, E.; Wilsmann, K.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., GE, 32, 8, 1982, 899
 Title:
            CNS Action Profile of Supidimide Compared with Other
            Sedative-Tranquilizing Drugs
 Abstract:
 CNR:
            5734292


 Author:
            Srivastava, V. K.; Satsangi, R. K.; Kishore, K.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 32, 12, 1982, 1512-1514
 Title:
            2-(2'-Hydroxyphenyl)-4-aryl-1,5benzodiazepines as CNS Active Agents
 Abstract:
            1-Aryl-3(2'-hydroxyphenyl)-propane-1,3-diones (III) have been
            prepared by the Baker-Venkataraman transformation of the
            corresponding 2-substituted benzoyloxyacetophenones (II).The
            aforesaid propane-1,3-diones (III) were condensed with o-phenylene
            diamine to give eight benzodiazepines (IV) which have been found to
            be very good MAO inhibitors (in vitro), and anticonvulsant and hypnotic
            (in vivo) agents.Some chemical leads on pharmacological activities
            have been observed. - Key words: 1,5-Benzodiazepines, derivatives .
            2-(2'-Hydroxyphenyl)-4-aryl-1,5-benzodiazepines, pharmacology,
            synthesis
 CNR:
            5734304

 Author:
            Sathi, Garima; Gujrati, Vibha R.; Nath, Chandishwar; Agarwal, Jagdish
            C.; Bhargava, Krishna P.; Shanker, Kripa
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), EN, 315, 7, 1982,
            603-609
 Title:
            Synthesis and Pharmacological Evaluation of New Ethyl Esters of
            N-Acyl Amino Acids as CNS Agents
 Abstract:
            The ethyl esters 1a-1j and 2a-2j of N-acyl amino acids were
            synthesized by the DCC method.The compounds were screened for
            their monoamine oxidase (MAO) inhibitory activity (in vitro) and various
            CNS activities (in vivo).Some compounds showed promising MAO
            inhibitory and anti-depressant activities.The compounds did not
            produce acute neurological deficits and have low toxicity.
 CNR:
            5748384

 Author:
            Agarwal, Rajesh; Misra, Shobha; Satsangi, Rajiv K.; Tiwari, Shiva S.
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), EN, 315, 2, 1982,
            142-146
 Title:
            Synthesis and CNS Activity of N,N-Disubstituted
            1-(Aminomethyl)-5-alkyl-3-(aryloxyacetylhydrazono)indolin-2-ones
 Abstract:
            Isatin and 5-methylisatin were condensed with various
            aryloxyacetylhydrazides to furnish the
            3-(aryloxyacetylhydrazono)-5-alkylindolin-2-ones 1-4.When 1-4 were
            subjected to Mannich reaction, the N,N-disubstituted
            1-(aminomethyl)-5-alkyl-3-(aryloxyacetylhydrazono)indolin-2-ones 5-8
            were obtained.The compounds were CNS active and relatively
            non-toxic (albino mice).
 CNR:
            5748455

 Author:
            Knabe, Joachim; Buech, Horst P.; Reinhardt, Joerg
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), GE, 315, 10, 1982,
            832-839
 Title:
            Derivatives of Barbituric Acid, XXXII: CNS Activity of Racemic and
            Optically Active Barbituric Acids with Basic Substituents
 Abstract:
            Out of the 5-piperidinobarbituric acids 3a-3e, the 5-pyrrolidinobarbituric
            acids 4b, 4h and the 5-dimethylaminobarbituric acid 5d only the
            barbituric acids having a cyclic basic substituent show CNS activity, as
            was shown in pharmacological studies.Quantitative and qualitative
            differences of the activity are observed depending on the
            stereochemistry of the compounds.These differences relate with
            findings obtained with conventional barbituric acids previously
            investigated by our group.
 CNR:
            5748922

 Author:
            Chaurasia, M. Ram; Sharma, Surendra K.
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), EN, 315, 4, 1982,
            377-381
 Title:
            Synthesis of Some New 4(3H)-Quinazolinones as Potential CNS
            Depressants
 Abstract:
            Several 6,8-disubstituted 2-methyl 1 and
            2-styryl-3-<(substituted)-benzothiazol-2-yl>-4(3H)-quinazolinones 2
            have been prepared.Some of them were tested for CNS depressant
            activity on mice and found to be active.
 CNR:
            5776529

 Author:
            Woodward, J. K.; Munro, N. L.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 32, 9a, 1982, 1154-1156
 Title:
            Terfenadine, the First Non-sedating Antihistamine
 Abstract:
            a-<4-(1,1-Dimethylethyl)phenyl>-4-(hydroxydiphenylmethyl)-piperidinebutanol
            (terfenadine, RMI 9918, Triludan, Teldane, resp.) is a potent antagonist of
            histamine H1-receptor-mediated responses both in vitro and in vivo; no
            anticholinergic, antiserotonergic or antiadrenergic effects can be demonstrated
            with terfenadine.In vitro mechanism studies suggest that terfenadine
            antagonizes histamine in a dualistic manner: competitive at concentrations of
            3.16E-8 - 1E-7 mol/l and unsurmountable at concentrations of 3.16E-7 - 1E-6
            mol/l.In vitro and ex vivo experiments have shown terfenadine to
            associate/dissociate with histamine H1-receptors much more slowly than a
            classical competitive antihistamine, chlorpheniramine.Ex vivo experiments as
            well as radioactive disposition/autoradiographic studies have demonstrated
            that terfenadine or its metabolites do not readily penetrate into the brain, a
            finding which suggests an explanation for the lack of CNS effects in both
            animal and human studies.Clinically, terfenadine is effective against perennial
            allergic rhinitis, acute seasonal allergic rhinitis and allergic skin conditions
            while being devoid of CNS effects including sedation, psychomotor
            impairment or interaction with diazepam or alcohol.Thus, terfenadine is a new
            antihistamine with a completely different and novel profile from the "classical
            antihistamines" and as such should prove to have significant clinical
            advantages for the symptomatic treatment of histamine-associated disorders. -
            Key words: Antihistamines; H1-Antagonists; RMI 9918; Teldane; Terfenadine,
            review of results; Triludan
 CNR:
            5794841

 Author:
            Gibson, J. P.; Huffmann, K. W.; Newberne, J. W.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 32, 9a, 1982, 1179-1184
 Title:
            Preclinical Safety Studies with Terfenadine
 Abstract:
            Preclinical safety studies indicate that
            a-<4-(1,1-dimethylethyl)phenyl<-4-(hydroxydiphenylmethyl)-1-piperidinebutanol
            (terfenadine, RMI 9918, Triludan, Teldane, resp.) is a relatively nontoxic drug in
            animals.Oral LD50 values were approximately 5000 mg/kg in mature mice and
            rats; intraperitoneal and intravenous values could not be established because of
            the low solubility of the compound.In chronic studies rats and mice tolerated 100
            mg/kg/day in the diet for 1.5 to 2 years without adverse effects, while
            150mg/kg/day of more caused some degree of reduction of body weight gain
            without evidence of histopathologic or clinical changes.Dogs tolerated single
            daily oral doses of 30 mg/kg/day for up to 2 years without effect, whereas weight
            loss, emesis and CNS effects were observed in some dogs at 80
            mg/kg/day.Daily doses of 300 mg/kg did not affect the fertility of male or female
            rats or cause any dominant lethal effects, but did cause maternal toxicity as
            shown by reduced implants and higher post-implantation losses; however these
            effects did not occur at 150 mg/kg/day.Reduced weight gain and survival of 300
            mg/kg offsprings and reduced weight gain of 150 mg/kg offspring occurred only
            when the mothers remained on drug until weaning indicating a direct toxic effect
            on the offspring rather than any developmental abnormalities caused by in utero
            exposure.Dosages of up to 300 mg/kg/day were not teratogenic in either rats or
            rabbits, but were often lethal to rabbits.No evidence of mutagenic or
            carcinogenic potential was observed.These findings indicate that terfenadine
            has a lower toxicity potential than other antihistamines. - Key words:
            Antihistamines; H1-Antagonists; RMI 9918; Teldane; Terfenadine, preclinical
            safety studies; Triludan
 CNR:
            5794847

 Author:
            Barlow, J. L. R.; Beitman, R. E.; Tsai, T. H.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 32, 9a, 1982, 1215-1218
 Title:
            Terfenadine, Safety and Tolerance in Controlled Clinical Trials
 Abstract:
            a-<4-(1,1-Dimethylethyl)phenyl>-4-(hydroxydiphenylmethyl)-1-piperidinebutanol
            (terfenadine, RMI 9918, Triludan, Teldane, resp.) is a new histamine H1-receptor
            antagonist.In clinical trials, terfenadine has been studied extensively in adult
            patients and to a limited extent in children.Based on the results of the
            double-blind placebo controlled studies, the incidence of CNS depression
            (drowsiness, sleepiness, fatigue, weakness, lack of concentration,
            "fuzzy"/"blurred thinking") with doses of 120 mg/day or higher of terfenadine
            (12.6percent) was similar to that of placebo (11.4percent) while that of the
            comparative drugs such as chlorpheniramine (12 mg/day) or clemastine (2
            mg/day) in these studies ranged from 22percent to 26percent.The incidence of
            all other side effects, including other CNS effects such as headache and
            stimulation with terfenadine and the other antihistamines were not different from
            those with placebo except for dryness of the nose, mouth or throat.Dryness was
            reported in a greater percentage of patients given clemastine (4.6percent) or
            chlorpheniramine (4.5percent) than in those given terfenadine (2.6percent),
            d-chlorpheniramine (2.7percent) or placebo (2.2percent).It is concluded that the
            results of controlled clinical trials with terfenadine provide further evidence of the
            overall safety and lack of sedative effects of this drug. - Key words:
            Antihistamines; H1-Antagonists; RMI 9918; Teldane; Terfenadine, clinical
            pharmacology, review of results, safety, tolerance; Triludan
 CNR:
            5794859

 Author:
            Friderichs, E.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., GE, 32, 6, 1982, 613-620
 Title:
            Studies on the CNS Activity Profile of Thaliomide Analogs
 Abstract:
            CNS activity of thalidomide was compared with that of 5 analogs
            modified in the phthalimide or 2,6-dioxopiperidine moiety.All
            compounds had a qualitatively comparable profile of CNS-depressant
            actions.In low dosages spontaneous motor activity was depressed,
            threshold of barbiturate anaesthesia was lowered, and
            isolation-induced agression was inhibited.All compounds suppressed
            tonic convulsions induced by maximum electroshock.Only at high
            dosages muscle tone and body temperature were lowered.Protection
            against nicotine lethality revealed antagonistic activity at central
            nicotinergic synapses.Corresponding depression of peripheral
            ganglionic transmission was indicated by mydriatic and antidiarrhoeal
            activity.While thalidomide, supidimide, EM 8, and EM 255 did not
            induce anaesthesia up to highest of lethal-toxic doses, EM 136 and EM
            12 in accordance with common sedative-hydpnotic drugs induced loss
            of righthing reflex at high dosages.EM 136 differs from thalidomide
            only in that one oxygen group at the piperidine moiety is missing.This
            finding indicates that a minor structural change shifts CNS depresssion
            towards anaesthetic properties.A clearcut relation between structure
            and teratogenic activity had been established in this group or
            compounds, whereas CNS-depressant efficacy could not be
            unequivocally related to particular structural features. - Key words:
            CNS-activity; Sedative-hypnotic drugs; Supidimide; Thalidomide,
            analogs
 CNR:
            5795050

 Author:
            Wesemann, W.; Schollmeyer, J. D.; Sturm, G.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 32, 10, 1982, 1243-1245
 Title:
            Distribution of Memantine in Brain, Liver, and Blood of the Rat
 Abstract:
            The distribution of 1,3-dimethyl-5-aminoadamantane (DMAA, D-145,
            memantine, Memantine), a compound used in the treatment of CNS
            disorders, is investigated in liver, brain, and blood of the rat.The tissue
            concentration of memantine, is analyzed by gaschromatography after
            i.p. and p.o. administration.After i.p. application the blood levels are
            only about 1/10-1/20 of the concentrations found in liver and brain.The
            highest drug concentration in blood is obtained within the first 15 min,
            followed by liver and brain, 30 and 60 min after i.p. administration,
            respectively.The memantine concentration per g brain tissue is almost
            identical to the dose applied per g body weight.Lower brain levels are
            obtained if memantine is given p.o.However, in contrast to the rapid
            decrease after i.p. treatment, the plateau reached 1 h after p.o.
            administration does not level off within the next 3 h. - Key words: D-145
            .Memantine, tissue distribution .Memantine
 CNR:
            5797175

 Author:
            Osborne, N. N.; Beale, R.; Golombiowska-Nikitin, K.; Sontag, K.-H.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 32, 10, 1982, 1246-1255
 Title:
            The Effect of Memantine on Various Neurobiological Processes
 Abstract:
            Experiments are reported which show that
            1,3-dimethyl-5-aminoadamantane (DMAA, D-145, memantine,
            Memantine) does not influence the binding capacity of a variety of
            tritiated ligands to rat brain membranes thus suggesting that the drue
            does not interact with dopamine, opioid, GABA, a1- and a2-adrenergic
            receptors, but can influence with low potency 5-HT1
            receptors.Autoradiographical studies also show that memantine does
            not interfere with the specific uptake mechanism of various transmitter
            substance nor is 3H-memantine take up by any neuronal
            elements.Memantine at high concentrations was shown to release
            3H-monoamins which had previously been taken up by nervous tissue
            but the release process is independent of calcium ions and is not
            dose-dependent.The latter effect could be explained by CNS culture
            studies which show memantine to produce morphological changes in
            neurones and glia when present at concentrations greater than 50
            mmol/l. - Key words: D-145 .Memantine, binding studies .Memantine
            .Neurotransmitters
 CNR:
            5797176

 Author:
            Barnett, A.; Iorio, L. C.; Ongini, E.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 32, 11, 1982, 1452-1456
 Title:
            The Sedative-Hypnotic Properties of Quazepam, A New Hypnotic Agent
 Abstract:
            7-Chloro-1-(2,2,2-trifluoroethyl)-5-(o-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-thione
            (Sch 16134,quazepam) is a new hypnotic drug with demonstrated clinical efficacy.Quazepam
            has been shown in our laboratories to have potent hypnotic activity and fewer side effects at
            effective doses than furazepam, which was studied concurrently.Hypnotic potency was
            estimated in mice via antagonism of electroshock-induced convulsions (ECS), potentiation of
            hexobarbital-induced sleeping time, and chlorprothixene potentiation.The respective oral ED
            50's (95percent fiducial limits) in the 3 tests were 0.9 (0.4-2.0), 0.5 (0.3-0.8) and 0.05
            (0.02-0.08) mg/kg for quazepam and 1.6 (1.1-2.3), 0.6 (0.4-1.0) and 0.11 (0.07-0.42) mg/kg for
            flurazepam.The duration of action of quazepam as measured by antagonism of ECS in mice
            was similar to that of flurazepam at equi-effective doses but quazepam had a faster
            onset.When potential tolerance to hypnotic efficacy was studied, quazepam did not show
            tolerance after dosing 20 mg/kg p.o. twice daily (b.i.d,) for 5 days, whereas tolerance was seen
            with flurazepam at equi-effective doses b.i.d. for 5 days.In conscious, unrestrained squirrel
            monkeys and cats, quazepam produced sedation with less ataxia and less evidence of CNS
            stimulant action than flurazepam.On the basis of the aforementioned studies, quazepam
            should be an effective hypnotic with less potential for ataxia, paradoxical excitation, and
            tolerance than flurazepam. - Key words: Benzodiazepines .Flurazepam .Hypnotics .Quazepam,
            pharmacology .Sch 16134
 CNR:
            5797219

 Author:
            Ongini, E.; Parravicini, L.; Bamonte, F.; Guzzon, V.; Iorio, L. C.; Barnett, A.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 32, 11, 1982, 1456-1462
 Title:
            Pharmacological Studies with Quazepam, a New Benzodiazepine Hypnotic
 Abstract:
            7-Chloro-1-(2,2,2-trifluoroethyl)-5-(o-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-thione
            (Sch 16134, quazepam) demonstrated high safety and effective hypnotic properties.Toxicity of
            quazepam in mice was extremely low at the largest doses administrated of 5000 mg/kg p.o.
            and 1370 mg/kg i.p. as compared to LD 50 values for flurazepam of 756 (635-889) mg/kg p.o.
            and 254 (234-280) mg/kg i.p.In cats, quazepam did not produce overt toxicity even at the
            highest dose administered, 1000 mg/kg p.o., wheras death occurred after the administration of
            flurazepam at a median dose of 250 mg/kg p.o.In addition, flurazepam produced central
            excitation and convulsions.Quazepam did not affect hemodynamic parameters in conscious
            dogs and anesthetized cats.Autonomic functions were virtually unaffected by the drug in
            anesthetized cats.In interaction studies in mice, quazepam did not interact with cimetidine
            while it potentiated the sedative activity of a-methyldopa, ethanol and propranolol.The CNS
            depressant properties of quazepam were further investigated by studying its effects on
            spontaneous motor activity in mice and EEG pattern in immobilized cats.In mice, quazepam
            reduced locomotor activity at doses which did not impair motor coordination thus differing from
            flurazepam which did.In the EEG study, quazepam produced a slow wave EEG pattern
            comparable to that of physiological sleep, while flurazepam induced a similar EEG activity
            which alternated with a fast frequency pattern of moderate amplitude.Quazepam also showed
            potent anticonvulsant activity.These results suggest that quazepam is likely to be a safe and
            effective sleep-promoting agent. - Key words: Benzodiazepines .Flurazepam .Hypnotics
            .Quazepam, pharmacology .Sch 16134
 CNR:
            5797220

 Author:
            Varma, Rajendra S.; Pandey, Rajnish K.
 Reference:
            Journal, JICSAH, J.Indian Chem.Soc., EN, 59, 10, 1982, 1174-1176
 Title:
            Synthesis of 3-(p-Fluoro)benzoylhydrazono-5-substituted-2-indolinones
            as Potential Biologically Active Agents
 Abstract:
            Different 5-substituted isatins have been condensed with p-fluoro benzoic
            acid hydrazide to furnish
            3-(p-fluoro)benzoylhydrazono-5-substituted-2-indolinones (I).Similarly,
            reaction of N-methyl-5-substituted isatins with p-fluorobenzoic acid
            hydrazide yielded
            1-methyl-3-(p-fluoro)benzoylhydrozono-5-substituted-2-indolinones
            (II).When I were subjected to Mannich reaction
            1-aminomethyl-3-(p-fluoro)benzoylhydrazono-5-substituted-2-indolinones
            (III) were obtained.These compounds were screened for antibacterial
            activity against B. megaterium, X. malvacearium, E. coli and B. subtilis as
            well as for CNS activity.
 CNR:
            5861140

 Author:
            Patra, Amarendra; Mitra, Alok K.; Mukhopadhyay, Apurba K.
 Reference:
            Journal, JICSAH, J.Indian Chem.Soc., EN, 59, 5, 1982, 660-662
 Title:
            Carbon-13 NMR Signals of Some Phenothiazine Derivatives
 Abstract:
            Carbon-13 nmr signal assignments of the CNS depressants
            promethazine (1), trimeprazine (2), chlorpromazine (3),
            prochlorperazine (4), triflupromazine (5), isothiopendyl (6) and some of
            their salts are reported.C-H coupling constant (1J and 3J)
            measurements have also been made.
 CNR:
            5861727

 Author:
            Mody, M. K.; Prasad, A. R.; Ramalingam, T.; Sattur, P. B.
 Reference:
            Journal, JICSAH, J.Indian Chem.Soc., EN, 59, 6, 1982, 769-770
 Title:
            Synthesis and Pharmacology of
            2-Aryl-5-Aryloxyalkyl-s-Triazolo<3,4-b>-1,3,4-Thiadiazoles
 Abstract:
            A number of new s-triazolo<3,4-b>-1,3,4-thiadiazoles carrying aryl
            moiety at 2 position and aryloxyalkyl group at 5 position were
            synthesised and evaluated for their pharmacological activity.Some
            compounds exhibited strong CNS depressant, mild
            hypocholesterolemic and hypotensive action in experimental animals.
 CNR:
            5861743

 Author:
            Harland, Ernest C.; Murphy, James C.; Elsohly, Hala; Greubel,
            Deborah; Turner, Carlton E.; Watson, E. S.
 Reference:
            Journal, JPMSAE, J.Pharm.Sci., EN, 71, 6, 1982, 677-679
 Title:
            Biological Effects of Nonalkaloid-Containing Fractions of Erythroxylon
            coca
 Abstract:
            Water soluble nonalkaloid fractions of Erythroxylon coca were
            screened in mice for their effects on oxygen utilization and central
            nervous system (CNS) activity.The fractions were screened in dogs for
            cardiovalcular, blood glucose, and respiratory changes.No CNS effects
            were demonstrated in mice; however, there was a reduction in the
            oxygen utilization rate.Intravenous administration of the extract to dogs
            produced hyperglycemia, a reduction in heart rate, and a decrease in
            blood pressure.No substantial change in the respiratory rate and tidal
            or minute volumes were observed.
 CNR:
            5889261

 Author:
            Zirvi, K. A.; Fakouhi, T.
 Reference:
            Journal, FRPSAX, Farmaco Ed.Sci., EN, 37, 5, 1982, 335-342
 Title:
            SYNTHESIS AND NEUROPHARMACOLOGY OF BUTYRYLUREAS
 Abstract:
            Nineteen urea derivatives of butyric acid were synthesized and
            examined for general depressant properties, barbiturate potentiation,
            myorelaxant, antitremorine and anticonvulsant potencies.Water
            solubility does not play an important role in the activity of these
            compounds; however, other factors such as electron density and lipid
            solubility appear to be involved. 1-Butyryl-3-allylthiourea appears to be
            the most active CNS depressant, whereas, butyrylthiourea is the most
            active barbiturate potentiator.Butyrylurea, 1-butyryl-3-propylurea,
            1-butyryl-3-n-butylurea, 1-butyryl-3-t-butylurea,
            1-butyryl-3-allylthiourea, and 1-butyryl- 3-phenylurea appear to be the
            most active myorelaxants, while butyrylthiourea,
            1-butyryl-3-methylurea, 1-butyryl-3-ethylurea, 1-butyryl-3-ethylthiourea,
            1-butyryl-3-propylurea, 1-butyryl-3-n-butylurea, 1-butyryl-3-t-butylurea,
            1-butyryl-3-allylurea, 1-butyryl-3-(1-adamantyl)urea and
            1-butyryl-3-(2,3-xylyl)urea are the most active against
            penthylenetetrazole-induced convulsions. 1-Butyryl-3-ethylurea,
            1-butyryl-3-n-butylurea, 1-butyryl-3-phenylurea,
            1-butyryl-3-(2,3-xylyl)urea and 1-butyryl-3-(a-naphthyl)thiourea are also
            slightly active oxotremorine antagonists.
 CNR:
            5937553

 Author:
            Agarwal, Rajesh; Shukla, Mahesh K.; Satsangi, Rajiv K.; Chaudhary, Chapla
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 20, 8, 1981, 680-682
 Title:
            Synthesis of
            1-<p-<3-(2'-Oxo/thiobenzoxazolinylmethyl)amino>benzoyl>-4-aryl/methyl-piperazines
            as CNS Active Agents
 Abstract:
            The title compounds (IIIa-h) have been synthesised by the Mannich reaction of
            benzoxazolin-2-one/thione with 4-substituted 1-(p-aminobenzoyl)piperazines (IIa-d),
            wich in turn have been prepared by the reduction of the respective 4-substituted
            1-(p-nitrobenzoyl)piperazines (I).All the compounds of the series III are found to be
            potent CNS stimulants and nontoxic.
 CNR:
            5576065

 Author:
            Agarwal, Rajesh; Satsangi, R. K.; Tiwari, S. S.
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 20, 12, 1981, 1099-1100
 Title:
            Synthesis and CNS Activity of 1,5-Disubstituted
            -3-(4'-acetamidophenoxyacetylhydrazono)indolin-2-ones
 Abstract:
            5-Substituted-indoline-2,3-diones on condensation with
            4-acetamidophenoxyacetylhydrazine give
            5-substituted-3-(4'-acetamidophenoxyacetylhydrazono)indolin-2-ones (I)
            which undergo Mannich reaction with secondary amines, to give
            1,5-disubstituted-3-(4'-acetamidophenoxyacetylhydrazono)indoline-2-ones
            (II).Compounds II have been found to show CNS activity in albino mice
 CNR:
            5577129

 Author:
            Maerki, W.; Spiess, J.; Tache, Y.; Brown, M.; Rivier, J. E.
 Reference:
            Journal, JACSAT, J.Amer.Chem.Soc., EN, 103, 11, 1981, 3178-3185
 Title:
            Total Solid-Phase Synthesis of Porcine Gut Gastrin Releasing Peptide (GRP), a Mammalian Bombesin
 Abstract:
            Recently, gastrin releasing peptide (GRP),
            Ala-Pro-Val-Ser-Val-Gly-Gly-Gly-Thr-Val-Leu-Ala-Lys-Met-Tyr-Pro-Arg-Gly-Asn-His-Trp-Ala-Val-Gly-His-Leu-Met-NH2,
            a mammalian bombesin, was isolated from porcine gastric mucosa and sequenced by McDonald et al.9 This
            polypeptide was manually synthesized by solid-phase metodology, using a benzhydrylamine-styrene-1percent
            divinylbenzene copolimer.Deprotection and cleavage from the resin were accomplished by HF.The crude peptide was
            purified by gel filtration and reverce-phase, high-performance liquid chromatography (RP-HPLC).Homogeneity of the
            synthetic peptide was demonstrated by RP-HPLC, sequence analysis, peptide mapping, and amino acid analysis.The
            peptide was further characterized by thin-layer chromatography, paper electrophoresis, optical rotation, ultraviolet
            spectroscopy, and 300-MHz Fourier transform proton nuclear magnetic resonance spectroscopy.The circular
            dichroism spectra of GRP indicated that the polypeptide chain was largely random with no evidence for a-helical
            structure.The primary structure was confirmed by amino acid analysis of the tryptic peptide fragments, sequence
            analysis of GRP and its Met(O) derivative using a modified 890 C spinning-cup sequencer, and C-terminal end group
            determination.GRP released gastrin when administered systemically and decreased gastric acid secretion when
            given intracisternally in rats.GRP also mimicked CNS-mediated actions of bombesin to influence thermoregulation or
            glucoregulation, most likely because of the common C-terminal homology of these peptides.This assumption was
            supported by the observation that the synthetic acetylated octapeptide <Ac-His20>-GRP (20-27) showed
            pharmacological effects similar to those exhibited by GRP and amphibian bombesin.
 CNR:
            5627193

 Author:
            Hirai, Kentaro; Ishiba, Teruyuki; Sugimoto, Hirohiko; Fujishita, Toshio;
            Tsukinoki, Yuji; Hirose, Katsumi
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 24, 1, 1981, 20-27
 Title:
            Novel Peptidoaminobenzophenones, Terminal N-Substituted
            Peptidoaminobenzophenones, and
            N-(Acylglycyl)aminobenzophenones as Open-Ring Derivatives of
            Benzodiazepines
 Abstract:
            Peptidoaminobenzophenones (1), terminal N-substituted
            peptidoaminobenzophenones (14), and
            acylglycylaminobenzophenones (16) were prepared as a novel series
            of ring-opened derivatives of 1,4-benzodiazepine.Z-Gly- and
            Z-Ala-N-methylaminobenzophenones (4) were treated with HBr-HOAc
            to give Gly- and Ala-N-methylaminobenzophenone hydrobromides
            (8).Reaction of 8 with chloroacetyl chloride in dimethylformamide
            (DMF) or hexamethylphosphoramide (HMPA) gave chloracetamide
            (13), which was allowed to react with various amines to afford a
            number of terminal N-substitutedderivatives (14).Reaction of 8 with
            various acyl halides in HMPA or DMF gave a number of
            acylglycyl-N-methylaminobenzophenones
            (16).Peptidoaminobenzophenones (1) were also prepared by several
            convenient methods.Many of these compounds exhibited high CNS
            activity in animals when given orally.In antianxiety activity the potency
            of some compounds is equal to or higher than that of diazepam.
 CNR:
            5637525

 Author:
            Tenthorey, Paul A.; Block, Alan J.; Ronfeld, Robert A.; McMaster, Paul
            D.; Byrnes, Eugene W.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 24, 7, 1981, 798-806
 Title:
            New Antiarrhythmic Agents. 6. Quantitative Structure-Activity
            Relationships of Aminoxylidides
 Abstract:
            The synthesis and pharmacological evaluation of primary and tertiary
            aminoxylidides with the amino group in the 2-7 position of the acyl
            chain are described. 2,6-Xylidine was acylated with haloacyl halides
            and converted to the target compounds by direct amination or by the
            Gabriel procedure.Alternatively, 2,6-xylidine was coupled with keto
            acids, and the ketoxylidides were converted to the amines by reductive
            amination.The target compounds were evaluated in mice both for
            antiarrhythmic efficacy against chloroform-induced tachycardia and for
            central nervous system toxicity.Experimentally determined values of
            partition coefficients and pKa values were used for quantitative
            structure-activity analyses.While the antiarrhythmic activity could be
            described as a function of log P alone, the CNS toxicity was best
            described as a function of both log P and pKa.The results suggest that
            antiarrhythmic potency can be increased by increasing lipophilicity,
            while the therapeutic index can be improved by increasing the pKa.
 CNR:
            5637653

 Author:
            McMaster, Paul D.; Byrnes, Eugene W.; Block, Alan J.; Tenthorey, Paul
            A.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 24, 1, 1981, 53-58
 Title:
            New Antiarrhythmic Agents. 5. a-Aminoaceto-2,6-xylidides with
            Functionalized Amide Alkyl Substituents
 Abstract:
            The synthesis of aminoaceto-2',6'-xylidides substituted on the amide
            nitrogen with 2-(diethylamino)ethyl, 2-aminoethyl, 2-hydroxyethyl, and
            2-ethoxyethyl groups is described.The 2-aminoethyl derivatives were
            prepared by treatment of N-(2-phthalimidoethyl)-2',6'-xylidine with
            chloroacetyl chloride, followed by treatment with either potassium
            phthalimide or diethylamine.Hydrazinolysis of the phthalimides
            liberated the free amines.The remaining target compounds were
            produced by alkylation of lidocaine or of
            2-phthalimidoaceto-2',6'-xylidide with the appropriate halideand
            sodium hydride, followed by hydrazinolysis where necessary.All target
            compounds were evaluated for antiarrhythmic efficacy against
            chloroform-induced ventricular tachycardia, as well as for acute CNS
            toxicity in mice.Most of the target compounds were more potent than
            the corresponding secondary amides and had improved therapeutic
            margins toward CNS toxicity.The diamines
            N-(2-aminoethyl)-2-aminoaceto-2',6'-xylidide (13) and
            N-(2-aminoethyl)-2-(diethylamino)aceto-2',6'-xylidide (29) are
            especially promising in this respect.Several compounds were tested
            as spinal anesthetics.
 CNR:
            5638055

 Author:
            Bennett, G. B.; Babington, R. G.; Deacon, M. A.; Eden, P. L.; Kerestan,
            S. P.; et al.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 24, 5, 1981, 490-496
 Title:
            A Potent, New, Sedative-Hypnotic Agent:
            5,7-Dihydro-5,5,7,7-tetramethyl-3-(3-nitrophenyl)furo<3,4-e>-as-triazine
            4-Oxide
 Abstract:
            A series of 3-phenylfuro<3,4-e>-as-triazines was prepared and their
            CNS sedative-hypnotic activity was measured.From this series,
            5,7-dihydro-5,5,7,7-tetramethyl-3-(3-nitrophenyl)-furo<3,4-e>-as-triazine
            4-oxide (5b) emerged as a potent sedative-hypnotic of unique
            pharmacological properties.A description of the syntheses and a
            discussion of the relationship between structure and CNS activity of
            these compounds, in particular of compound 5b, are presented.
 CNR:
            5638119

 Author:
            Shukla, J. S.; Ahmad I.
 Reference:
            Journal, PHARAT, Pharmazie, EN, 36, 5, 1981, 327-328
 Title:
            Search for Newer Substituted Phenoxyacetylethyleneimines as
            Possible CNS, MAO and Anticonvulsant Agents
 Abstract:
            Various substituted phenoxyacetic acids were converted into the acid
            chlorides, which react with ethyleneimine in pyridine to give the
            desired product.These compounds were evaluated for central nervous
            system (CNS) activity.Some of the compounds at a concentration of
            1E-3 mol/l inhibited rat brain monoamine oxidase (MAO) in vitro and
            provided protection against pentylenetetrazole-induced convulsions in
            mice.
 CNR:
            5685577

 Author:
            Ong, Helen H.; Profitt, James A.; Anderson, V. Brian; Kruse, Hansjoerg;
            Wilker, Jeffrey C.; Geyer, Harry M.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 24, 1, 1981, 74-79
 Title:
            Novel Tetracyclic Spiropiperidines. 1.
            3-Aryl-1,3-dihydrospiro<benzo<c>thiophene-1,4'-piperidines> as
            Potential Antidepressants
 Abstract:
            A series of
            3-aryl-1,3-dihydrospiro<benzo<c>thiophene-1,4'-piperidine>
            derivatives was synthesized and evaluated pharmacologically for
            potential psychotropic activity.Potent antidepressant-like activity was
            noted throughout the series, as assessed by tetrabenazine (TBZ)
            ptosis prevention in mice and potentiation of 5-hydroxytryptophan
            (5-HTP) induced behavioral effects in rats.A possible therapeutic
            advantage of the title compounds appears to be the overall low
            anticholinergic potential in comparison with the classic tricyclic
            antidepressants.Several congeners withnuclear halogen substitution
            also exhibited CNS stimulant properties, as evidenced by their ability
            to induce a dopamine agonist-like stereotypy and to increase the
            spontaneous motor activity in mice.
 CNR:
            5745579

 Author:
            Havanur, Shambhuling B.; Badami, Bharati V.; Puranik, Gurubasav S.
 Reference:
            Journal, ARPMAS, Arch.Pharm.(Weinheim Ger.), EN, 314, 6, 1981,
            503-507
 Title:
            Synthesis and Central Nervous System Depression Properties of
            3-<(1'-Pyrazolyl)phenyl>sydnones
 Abstract:
            Some hitherto unknown 3-<o-(1-pyrazolyl)phenyl>sydnones were
            synthesized.Together with some 3-<p-(1-pyrazolyl)phenyl>sydnones
            they were studied for their CNS depression activity.
 CNR:
            5749112

 Author:
            Clough, D. P.; Hatton, R.; Pettinger, S. J.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 31, 10, 1981, 1698-1703
 Title:
            A New centrally Acting Antihypertensive (ICI 106270) which Separates
            Antihypertensive Effects from Sedation
 Abstract:
            1.
            6-(2-Chloro-6-fluorophenyl)-2,3,6,7-tetrahydro-5H-pyrrolo-<1,2-a>-imidazole
            hydrobromide (ICI 106270) has been developed with the objective of
            achieving satisfactory blood pressure (BP) reduction while minimising the
            side-effects seen with clonidine. 2.In the pentobarbitone sodium
            anaesthetised rat the dose of ICI 106270 to lower BP by 20 mmHg (ED 20)
            was 5.45 mg/kg i.v. (ED 20 clonidine 1.18 mg/kg i.v.).In conscious
            spontaneously hypertensive rats 10 mg/kg orally of ICI 106270 lowered BP
            by 70+/-12.2 mmHg.A similar fall of BP of 67+/-6.5 mmHg was seen with 1
            mg/kg of clonidine orally. 3.In conscious renal-hypertensive dogs ICI 106270
            is 2-3 times less potent than clonidine when dosed either p.o. or i.v. but was
            equipotent with clonidine at lowering BP when administered into a lateral
            cerebral ventricle. 4.Clonidine (250-750 mg/kg) administered i.p. in rats
            caused a marked potentiation of anaesthesia induced by pentobarbitone.ICI
            106270 similarly administered in the same doses was without effect. 5.In a
            test for locomotor activity the ED 50 (dose to reduce locomotor activity by
            50percent) was 15.3 mg/kg i.v. for clonidine and 237.5 mg/kg i.v. for ICI
            106270.On oral administration the ED 50 for clonidine was 26 mg/kg and for
            ICI 106270 it was 2.14 mg/kg. 6.In the chloralose anaesthetised cat pre- and
            post-ganglionic sympathetic efferent nerve activity was reduced by ICI
            106270 in doses which also reduced BP. 7.The hypotensive effect of i.v.ICI
            106270 in anaesthetised rats was antagonised by the a-adrenoceptor
            antagonists yohimbine and piperoxan. 8.These results indicate that ICI
            106270 is a potent antihypertensive with a similar mechanism of action to
            clonidine although it is relatively less sedative.It is an a-stimulant and its site
            of action is probably within the CNS. - Keywords: a-Adrenergic agonists;
            Antihypertensives;
            6-(2-Chloro-6-fluorophenyl)-2,3,6,7-tetrahydro-5H-pyrrolo-<1,2-a>-imidazole
            hydrobromide; Clonidine; ICI 106270
 CNR:
            5792711

 Author:
            Chodera, A.; Cenajek, D.; Mazurek, K.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 31, 1, 1981, 61-63
 Title:
            Interaction of Parachlorphenylalanine, Mianserine and Danitracen with
            Amphetamine
 Abstract:
            Three antiserotonin compounds, p-chlorphenylalanine, mianserine
            and danitracen, were investigated for their influence on amphetamine
            stereotypy in correlation with concentration of this amine in blood
            serum and brain tissue.A positive correlation (decrease of stereotypy
            as well as the concentration of amphetaminein serum and brain) was
            found only for danitracen. p-Chlorphenylalanine and mianserine
            premedication decreased serum and brain tissue concentration of
            amphetamine, but enhanced amphetamine stereotypy effect.It is
            assumed that in the mixed pharmacodynamic-pharmacokinetic
            interaction in the case of mianserine and p-chlorphenylalanine the
            pharmacodynamic component (inhibition of the serotoninergic system
            in CNS) prevails, whereas in the case of danitracen the
            pharmacokinetic effect was superior. - Key words: Amphetamine;
            Antiserotonin drugs; Danitracen; Mianserine; Parachlorphenylalanine
 CNR:
            5795338

 Author:
            Hill, R. C.; Foote, R. W.; Roemer, D.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 31, 5a, 1981, 873-882
 Title:
            The Pharmacodynamic Properties of Fluproquazone
 Abstract:
            4-(p-Fluorophenyl)-1-isopropyl-7-methyl-2(1H)-quinazolinone
            (fluproquazone) is a potent analgesic and antipyretic compound with
            anti-inflammatory properties.It is effective in a variety of animal
            species, is active after oral and parental administration and has a
            duration of action of several hours.Fluproquazone is many times more
            potent than acetylsalicylic acid (ASA) and generally resembles the
            clinically active ibuprofen and indoprofen in its pharmacodynamic
            effects.Fluproquazone is a very strong inhibitor of collagen and
            arachidonic acid-induced platelet aggregation.It causes mild CNS
            depressant effects in rodents only in very high doses and does not
            produce physical dependence when administered i.v. over a period of
            4 weeks to rhesus monkeys.In the anaesthetised dog, fluproquazone
            causes minimal cardiovascular changes.In fasted rats, fluproquazone
            is 3 times more ulcerogenic than ASA and ibuprofen and about half as
            potent as indoprofen whereas after repeated administration for five
            consecutive days, fluproquazone is by far the least toxic of the four
            compounds tested.At three times the acute UD50 fluproquazone does
            not produce any petechial hemorrhages and even after repeated
            administration of over six times the acute UD50 it only causes tiny
            gastric lesions.Comparison of the doses of the test compounds
            needed to cause analgesia and to inhibit yeast-induced pyrexia with
            the doses required to produce gastric lesions after acute and following
            repeated administration in the rat clearly shows that fluproquazone has
            the greatest safety margin.It is evident from the results that the
            pharmacodynamic effects of fluproquazone are due to a marked
            inhibition of the synthesis of prostaglandins and their metabolites as
            the order of potency of fluproquazone and the three reference
            compounds in the prostaglandin synthetase assay correlates
            reasonably well with the rank order recorded in other tests. - Key
            words: Analgesics; Fluproquazone, pharmacodynamics,
            pharmacology; Tormosyl
 CNR:
            5796126

 Author:
            Janicki, C. A.; Walking, W. D.; Erlich, R. H.; Bainbridge, C. A.
 Reference:
            Journal, JPMSAE, J.Pharm.Sci., EN, 70, 7, 1981, 778-780
 Title:
            Xilobam: Analysis, Determination of Decomposition Products, and
            Assessment of Stability
 Abstract:
            A stability-indicating UV assay was developed for xilobam, a member
            of a new class of CNS agents.The method was specific, precise, and
            accurate.TLC and high-pressure liquid chromatogryphy were used to
            support method specificity.Xilobam is sensitive to heat, moisture, and
            basic conditions.The degradation products were identified as
            N-methylpyrrolidone, 2,6-dimethylaniline, and
            N,N'-bis(2,6-dimethylphenyl)urea.At high temperatures, the
            incorporation of molecular sieves into glass bottles of xilobam tablets
            was effective in preventing decomposition caused by moisture or
            volatile decomposition products.
 CNR:
            5799124

 Author:
            Gras, J.; Basi, N.; Zapatero, J.; Bermejo, P.; Gimenez, P.; et al.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 31, 10a, 1981, 1808-1816
 Title:
            Pharmacological Activities and Side Effects of Plafibride
 Abstract:
            This paper reports on pharmacological properties of
            N-2-(p-chlorophenoxy)-isobutyryl-N'-morpholinomethylurea (plafibride,
            ITA 104) and its possible side effects.This work was carried out on
            CNS, ANS and PNS, cardiovascular system, respiratory and
            gastroenteric apparatus as well as antiinflammatory activity and gastric
            tolerance.The most evident secondary effects were: a certain sedation,
            as a light tranquillizing agent, a hypothermic effect when it was
            administered at high doses, a certain b-blocking and antiarrythmic
            activity probably due to its local anaesthetic action.All the side effects
            appeared at high doses, much higher than the therapeutic ones. - Key
            words: Hypolipemic drugs; ITA 104; Plafibride, pharmacology, side
            effects
 CNR:
            5832258

 Author:
            Nakao, K.; Wakabayashi, T.; Sugiyama, K.; Taki, T.; Sumigama, S.; Chiba T.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 31, 8, 1981, 1220-1225
 Title:
            Subacute and Chronic Toxicity Studies in Rats and Dose Range Finding Study
            in Dogs by Oral Administration of Azelastine
 Abstract:
            The antiallergic agent
            4-(p-chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1-(2H)-phthalazinone
            hydrochloride (azelastine) was administered p.o. to rats and dogs in order to
            determine its subacute or chronic toxicity.In the subacute toxicity study it was
            administered at oral doses of 3, 10, 30 and 100 mg/kg for 5 consecutive weeks
            to rats.The 3 and 10 mg/kg groups were free of particular drug effects.Symptoms
            of depression of the central nervous system were recognized in the 100 mg/kg
            group.In this group 4 out 20 animals died.Further, in the 30 and 100 mg/kg
            groups, alkaline phosphatase and GPT were elevated and there was an
            increase in urine volume.In the chronic toxicity study azelastine was
            administered in oral doses of 1, 3, 10 and 30 mg/kg for 6 and 12 consecutive
            months in rats.A fatty change in centrolobular and mid-zonal liver cells was
            observed in male rats of the highest dose group in the 6- and 12-month'
            studies.Further there was an increase in urine volume after administration of 30
            mg/kg of the drug in both the 6- and 12-month' studies.In dogs a dose range
            finding study was performed with oral doses of 5, 20, 40 and 60 mg/kg
            azelastine for 5 consecutive weeeks.There was no appreciable drug effect in the
            lowest dose group.Symptoms of stimulation of the central nervous system were
            observed with 20 mg/kg or more.All animals in the 40 and 60 mg/kg group
            died.The ECG of some animals showed a prolongation of the QRS-complex
            and the Q-T interval.Microscopically, one animal each of the two higher dose
            groups revealed an increase of adipose cells in the interstitial tissue of the
            myocardium.In the present toxicological investigation after repeated oral
            administration to ratsand dogs azelastine has proved to be a substance of, in
            general, good tolerance.In higher doses, especially, sporadic impairment of the
            CNS was seen, in some cases histomorphologic alterations such as fatty
            changes of liver cells, and an insignificant increase of urine volume were
            observed.In the subacute study in rats the minimum toxic dose was found to be
            30 mg/kg, in the chronic studies of 6 and 12 months' duration it was 30 mg/kg.In
            dogs toxic symptoms are only to be expected with doses above 5 mg/kg.The
            margin between these toxic and the pharmocodynamic effective doses amount
            to more than one order of magnitude. - Key words: Antiallergics; Azelastine,
            dose range finding, toxicity studies, subacute and chronic
 CNR:
            5833947

 Author:
            Hopfner, R.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 31, 5a, 1981, 927-929
 Title:
            Comparison of the Analgesic Efficacy of Fluproquazone, Pentazocine
            and Placebo against Postoperative Pain in Neurosurgical Patients
 Abstract:
            A controlled, double-blind study was performed to compare the new
            analgesic 4-(p-fluorophenyl)-1-isopropyl-7-methyl-2(1H)-quinazolinone
            (fluproquazone) (in the form of 100 mg and 200 mg capsules) with
            pentazocine 50 mg and placebo in 138 patients with
            post-neurosurgical pain.The efficacy of the compounds was tested on
            the basis of response to the initial administration of the stated doses
            and to repeated doses, the number of which depended on the
            individual needs of the patients.The patients' response was evaluated
            by means of standardized interviews and the von Zerssen subjective
            rating questionnaire, which provides information on the patients'
            mental and emotional status.Fluproquazone 200 mg and pentazocine
            50 mg were equally effective.The effect of fluproquazone 100 mg was
            somewhat less marked but, nevertheless, significantly different from
            that of placebo.The importance of developing potent analgesics free of
            addiction potential as an alternative to the agents which act on the
            CNS is discussed. - Key words: Analgesics; Fluproquazone, efficacy,
            post-operative pain; Pentazocine; Tormosyl
 CNR:
            5834899

 Author:
            Graziani, G.; Cazzulani, P.; Barbadoro, E.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 31, 12, 1981, 2145-2151
 Title:
            Toxicological and Pharmacological Properties of Fenticonazole, a
            New Topical Antimycotic
 Abstract:
            The acute oral and subchronic (6 weeks) topical toxicity of
            a-(2,4-dichlorophenyl)-b,N-imidazolylethyl 4-phenylthiobenzyl ether
            nitrate (fenticonazole, Rec 15/1476) was studied in mice, rats, guinea
            pigs and beagle dogs.The acute oral LD50 in mice and rats was found
            to 3000 mg/kg, while the i.p. acute toxicity was 1191 mg/kg in mice
            and between 309 and 440 mg/kg in rats.The acute oral LD50 in beagle
            dogs was 1000 mg/kg.Percutaneous subchronic (6 weeks) toxicity was
            evaluated in guinea pigs and beagle dogs.Both species of animals
            exhibited no toxic effect attributable to the treatment with fenticonazole
            and no histopathologic changes were attributed to the drug
            treatment.Fenticonazole did not affect numerous pharmacological and
            physiological parameters (blood pressure, heart rate, pulmanory
            ventilation, nor did it interfere with the activity of histamine, adrenaline,
            noradrenaline and acetylcholine).It does not possess analgesic or
            antiinflammatory activity at high doses (100 mg/kg p.o.).In mice it
            exhibits a slight CNS depressant activity, milder than that of
            miconazole. - Key words: Antimicrobial agents * Antimycotics *
            Fenticonazole, pharmacology, toxycology * Rec 15/1476
 CNR:
            5835138

 Author:
            Grote, B.; Doenicke, A.; Kugler, J.; Suttmann, H.; Loos, A.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., GE, 31, 12a, 1981, 2224-2225
 Title:
            Intramuscular Application of Midazolam / Its effect upon CNS and respiration
 Abstract:
            8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo<1,5-a><1,4>benzodiazepine
            (midazolam, Ro 21-3981, Dormicum) is a benzodiazepine with a pronounced
            sleep-inducing effect.Deep-sleep stages and respiratory depressions were
            observed after 5 mg i.v.Whether and in what dosage midazolam can be safely,
            i.e. without continous monitoring, administered i.m. must be shown by the
            analysis of larger study populations.After i.m. injection, there is rapid onset of
            action leading to sleep stages which are comparable only with those hitherto
            observed after i.v. injection. - Key words: Anesthesiology * Benzodiazepines *
            CNS * Dormicum * Midazolam, effects upon CNS and respiration *
            Respiratory depression * Ro 21-3981
 CNR:
            5835151


 Author:
            Vincek, William C.; Martin, Billy R.; Aceto, Matio D.; Tripathi, Hem L.;
            May, Everette L.; Harris, Louis S.
 Reference:
            Journal, JPMSAE, J.Pharm.Sci., EN, 70, 11, 1981, 1292-1293
 Title:
            Synthesis of 4,4-Ditritio-(+)-nicotine: Comparative Binding and
            Distribution Studies with Natural Enantiomer
 Abstract:
            The preparation of 4,4-ditritio-(+)-nicotine (Vb) (specific activity 10.3
            Ci/mmole) from (+)-nicotine (Ib) via (-)-4,4-dibromocotinine (IIIb) is
            described.Although Ib is 10-30 times less potent than (-)-nicotine (Ia) in
            the CNS, its binding affinity for the crude mitochondrial or nuclear
            fraction of whole rat brain is only three times less than that of
            (Ia).However, distribution studies showed that the maximum brain
            levels of (-)-<3H>-nicotine are nearly twice those of (+)-<3H>-nicotine
            following administration of a 2-mg/kg dose.Binding affinity and
            disposition of the stereoisomers account for a portion of the
            pharmacological stereospecificity of nicotine.
 CNR:
            5836847

 Author:
            Sowell, J. Walter; Block, Alan J.; Derrick, Mary Elizabeth; Freeman,
            John J.; Kosh, Joseph W.; et al.
 Reference:
            Journal, JPMSAE, J.Pharm.Sci., EN, 70, 2, 1981, 135-140
 Title:
            Synthesis of Alkylaminoalkylamides of Substituted 2-Aminopyrroles as
            Potential Local Anesthetic and Antiarrhyhmic Agents I: a-Amines
 Abstract:
            The synthesis, local anesthetic and antiarrhythmic properties, and
            CNS toxicity of 19 2-(2-alkylaminoalkylamido)pyrroles are
            described.Most of the compounds exhibited local anesthetic activity by
            the guinea pig wheal test, and four showed activity comparable to or
            greater than that of lidocaine.Most compounds also exhibited
            antiarrhythmic activity; five compounds had activity comparable to that
            of lidocaine, and one was more potent.All compounds exhibiting
            antiarrhythmic activity also were toxic to the central nervous system.
 CNR:
            5837808

 Author:
            Joshi, Krishna C.; Pathak, Vijai N.; Garg, Urmila
 Reference:
            Journal, JICSAH, J.Indian Chem.Soc., EN, 58, 1981, 1180-1181
 Title:
            Possible Psychopharmacological Agents. Part XII - Synthesis and CNS
            Activity of Some Fluorine Containing
            2-Oxo-1-phenylpyrazolo<1,5-a>Pyrimidines
 Abstract:
            New fluorine containing
            5,7-disubstituted-1,2-dihydro-2-oxo-1-phenylpyrazolo<1,5-a>pyrimidines
            have been synthesized by the condensation of
            3-amino-1-phenyl-5-pyrazolone with fluorinated 1,3-diketones in acetic
            acid and characterized by ir. pmr and 19F nmr spectral studies.CNS
            activity of some representative compounds has also been evaluated and
            three compounds exhibited significant antiinflammatory
            activity.Analgesic and anticonvulsant activities were not found at dose
            levels at 200 and 112 mg/kg.
 CNR:
            5858129

 Author:
            Samant, S. D.; Kulkarni, R. A.
 Reference:
            Journal, JICSAH, J.Indian Chem.Soc., EN, 58, 1981, 692-694
 Title:
            Synthesis and Pharmacology of
            1-(4-Aryl-l-Piperazinyl-alkyl)-4-(4-Methoxyphenyl)
            Piperidine-2,6-Diones: Tranquilizers
 Abstract:
            1-(4-Aryl-1-piperazinylethyl/propyl)-4-(4-methoxyphenyl)
            piperidine-2,6-diones were prepared by condensing
            1-(w-aminoalkyl)-4-arylpiperazines with 3-(4-methoxyphenyl)pentane
            dioic anhydride in dry pyridene.These compounds showed mild CNS
            depressant action.Their antagonism of increased toxicity of
            amphetamine in mice was recorded.
 CNR:
            5862034

 Author:
            Ramalingam, T.; Deshmukh, A. A.; Sattur, P. B.; Sheth, U. K.; Naik, S.
            R.
 Reference:
            Journal, JICSAH, J.Indian Chem.Soc., EN, 58, 1981, 269-271
 Title:
            Synthesis and Pharmacology of 2,5-Disubstituted 1,3,4-Oxadiazoles
 Abstract:
            A series of new 2,5-disubstituted 1,3,4-oxadiazoles carrying
            1,2-diarylethyl/aryl oxyalkyl moieties at 2-position and phenyl, amino,
            mercapto, thioacetic acid or ethyl thioacetate groups at 5 position were
            synthesised and evaluated for their pharmacological activity.Some
            members exhibited mild to strong antiinflammatory and CNS
            depressant action in experimental animals.
 CNR:
            5863813

 Author:
            Sowell, J. Walter; Block, Alan J.; Derrick, Mary Elizabeth; Freeman,
            John J.; Kosh, Joseph W.; et al.
 Reference:
            Journal, JPMSAE, J.Pharm.Sci., EN, 70, 5, 1981, 537-541
 Title:
            Synthesis of Alkylaminoalkylamides of Substituted 2-Aminopyrroles as
            Potential Local Anesthetic and Antiarrhythmic Agents II: b-Amines
 Abstract:
            The synthesis, local anesthetic and antiarrhythmic properties, and
            CNS toxicity of 14 2-(3-alkylaminoalkylamido)pyrroles are
            described.Most of the compounds exhibited local anesthetic activity by
            the guinea pig wheal test, with seven showing comparable or greater
            activity than lidocaine.Most compounds also exhibited antiarrhythmic
            activity; three compounds had more potent activity than lidocaine.All
            compounds exhibited antiarrhythmic activity also were toxic to the
            CNS.However, two of the three compounds having greater activity than
            lidocaine possessed more desirable therapeutic indexes.
 CNR:
            5868362

 Author:
            Schlecker, Rainer; Franke, Albrecht
 Reference:
            Journal, LACHDL, Liebigs Ann.Chem., GE, 10, 1980, 1507-1511
 Title:
            Synthesis of 2,6,7,11b-Tetrahydro-1H-dibenzo<c,d,h>azulene and
            Some Derivatives
 Abstract:
            The title compound 10 is obtained by reduction of the ketone
            9.Compound 10 is deprotonated by butyllithium and reacted with
            halogenoalkylamines to yield compounds 5, which may possess
            CNS-activity.
 CNR:
            5556803

 Author:
            Moffett, Robert Bruce
 Reference:
            Journal, JHTCAD, J.Heterocycl.Chem., EN, 17, 1980, 341-350
 Title:
            Tetracyclic Heterocycles as CNS Agents
 Abstract:
            A considerable number of new tri and tetracyclic heterocycles (II) and
            open chain intermediates were synthesized.These were tested in a
            battery of assays designed to reveal central nervous system (CNS)
            activity.However, none showed useful activity greater than known
            analogs.
 CNR:
            5560855

 Author:
            Cervena, Irena; Hrubantova, Marta; Svatek, Emil; Holubek, Jiri; Ryska,
            Miroslav; et al.
 Reference:
            Journal, CCCCAK, Collect.Czech.Chem.Commun., EN, 45, 10, 1980,
            2688-2694
 Title:
            FLUORINATED ANALOGUES OF TRICYCLIC NEUROLEPTICS:
            6,9-DIFLUORO DERIVATIVE OF
            10-(4-METHYLPIPERAZINO)-10,11-DIHYDRODIBENZO<b,f>THIEPIN
 Abstract:
            The acid VI, obtained from 2,5-difluorothiophenol (IV) and
            (2-iodophenyl)acetic acid, afforded by cyclization with polyphosphoric
            acid 6,9-difluorodibenzo<b,f>thiepin-10(11H)-one (VII) in a satisfactory
            yield.Two further steps led to the chloro derivative X giving by a
            substitution reaction with 1-methylpiperazine the title compound III.This
            substance exhibits some 10percent incoordinating activity of the
            unsubstituted compound I and an indication of cataleptic activity, in
            contrast to the inactive analogous dichloro compound II.The bulky atom
            of chlorine in the vicinity of the methylpiperazine residue intereferes
            evidently with the CNS activity; the influence of the atom of fluorine is
            much less pronounced in this line.
 CNR:
            5561726

 Author:
            Moffett, Robert Bruce
 Reference:
            Journal, JHTCAD, J.Heterocycl.Chem., EN, 17, 1980, 753-758
 Title:
            Analogs of Hetecyclic CNS Agents
 Abstract:
            Thirty-five oxazoles, thiazoles, piperazines and related compounds,
            analogs of known CNS agents, were prepared and tested.Nonewere
            more active than the lead compounds.
 CNR:
            5563316

 Author:
            Kumar, Naresh; Dhaon, Madhup K.; Agrawal, Shiv K.; Saxena, Anil K.; Jain, Padam C.;
            Anand, Nitya
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 19, 12, 1980, 1087-1088
 Title:
            Agents Acting on CNS: Part XXXI - Synthesis of 2-Substituted
            1,2,3,5,11,11a-Hexahydro-6H-imidazo<5',1':6,1>pyrido<3,4-b>indoles
 Abstract:
            The title compounds have been prepared starting from methyl
            1,2,3,4-tetrahydropyrido<3,4-b>indole-3-carboxylate (1).Treatment of 1 with methanolic
            solution of ammonia and methylamine affords the amides 5 and 6 respectively which
            furnish the corresponding amines 9 and 10 by LiAlH4 reduction. 5 and 6 on treatment with
            HCHO gives 2-substituted oxoimidazopyridoindoles (7,8) while 9 and 10 give
            imidazopyridoindoles (11,12).Treatment of 9, 10 with carbon disulphide gives the 3-thio
            derivates (13,14). 9 on condensation with g-chloro-p-fluorobutyrophenone furnishes 15,
            which on ring closure with HCHO affords
            2-g-(p-fluorobenzoyl)propyl-1,2,3,5,11,11a-hexahydroimidazo<5',1':6,1>pyrido<3,4-b>indole
            (16).None of these compounds exhibits any noteworthy biological activity.
 CNR:
            5575623

 Author:
            Dhaon, Madhup K.; Kumar, Naresh; Agarwal, Shiv K.; Saxena, Anil K.;
            Jain, Padam C.; Anand, Nitya
 Reference:
            Journal, IJSBDB, Indian J.Chem.Sect.B, EN, 19, 10, 1980, 882-885
 Title:
            Agents Acting on CNS: Part XXX - Synthesis of 2-Substituted
            1,2,3,4,6,7,12,12a-Octahydropyrazino<2',1':6,1>pyrido<3,4-b>-indoles
 Abstract:
            A number of 2-substituted pyrazinopyridoindoles (3,6-12) have been
            prepared by the condensation of
            1,2,3,4,6,7,12,12a-octahydropyrazino<2',1':6,1>pyrido<3,4-b>indole (1)
            with appropriate halogen compounds.Treatment of 1 with ethylene
            oxide gives 4 which on condensation with p-fluorobenzoyl chloride
            yields 5.The corresponding
            2-g-(p-fluorobenzoyl)propyl-6-oxo-octahydropyrazinopyridoindole (14)
            is prepared by the oxidation of 1 with mercuric acetate followed by
            condensation of the resulting 6-oxo derivative (13) with
            g-chloro-p-fluorobutyrophenone.
            1-Oxo-2-substituted-pyrazinopyridoindoles (16-18) are prepared by the
            reaction of ethylene oxide on methyl
            1,2,3,4-tetrahydropyrido<3,4-b>indole-3-carboxylate followed by
            condensation of the resulting oxazino derivative (15) with
            amines.These compounds show tranquillizing, anti-inflammatory and
            diuretic activities.
 CNR:
            5577620

 Author:
            Fuyimoto, Masafumi; Tsukinoki, Yuji; Hirose, Katsumi; Kuruma, Kazuo;
            Konaka, Ryusei; Okabayashi, Tadashi
 Reference:
            Journal, CPBTAL, Chem.Pharm.Bull., EN, 28, 5, 1980, 1378-1386
 Title:
            Detection and Determination of Pharmacologically Active
            Benzodiazepines in Rat Brain after the Administration of
            2-o-Chlorobenzoyl-4-chloro-N-methyl-N'-glycylglycinanilide, using a
            Combination of High-Pressure Liquid Chromatography and
 Abstract:
            In the present work we attempted to detect and quantitate central
            nervous system (CNS)-active benzodiazepines in rat brain after
            administration of a peptido-aminobenzophenone.The results can be
            summarized as follows. 1.Radioreceptorassay (RRA) using
            (3)H-diazepam as the labeled ligand and rat-brain crude
            synaptosomes was a simple, reliable and sensitive assay method for
            benzodiazepines. 2.A benzene extract of a rat brain homogenate
            prepared 15 min after i.p. administration of
            2-o-chlorobenzoyl-4-chloro-N-methyl-N'-glycylglycinanilide (1) was
            subjected to high pressure liquid chromatography (HPLC).By RRA
            analysis of the eluated fractions, four benzodiazepines having high
            affinity for benzodiazepine receptors were detected. 3.Changes in the
            levels of each benzodiazepine in rat brains after i.p. administration of 1
            were determined by a combination of HPLC and RRA.The levels can
            account for the CNS activities of 1. 1 itself could not be detected
            throughout the experiments.These results strongly indicate that 1
            exerts its CNS activities through conversion into CNS-active
            benzodiazepines in vivo.Keywords --
            2-o-chlorobenzoyl-4-chloro-N-methyl-N'-glycylglycinanilide;
            benzodiazepine; high pressure liquid chromatography (HPLC);
            radioreceptorassay (RRA); HPLC-RRA; the benzodiazepine levels in
            rat brains
 CNR:
            5665225

 Author:
            Cointet, Paul; Grossi, Pierre-Jean; Pigerol, Charles; Broll, Madeleine;
            Eymard, Pierre
 Reference:
            Journal, EJMCA5, Eur.J.Med.Chem.Chim.Ther., FR, 15, 3, 1980,
            223-228
 Title:
            Synthese et proprietes pharmacologiques de thienyl-3 acetamides
            alpha-substitues
 Abstract:
            3-thienyl acetamids 4 have been synthesized starting from
            3-thienyl-acetonitrile or alkyl 3-thienylacetate.Pharmacological studies
            showed that some compounds displayed anticonvulsive and CNS
            depressant activities comparable to that of meprobamate.
 CNR:
            5679874

 Author:
            Law, Bay-Jong; Borne, Ronald F.
 Reference:
            Journal, EJMCA5, Eur.J.Med.Chem.Chim.Ther., EN, 15, 3, 1980,
            229-236
 Title:
            C.N.S. Activity of 2-azabicyclo <2.2.2> octane analogues of
            psychotomimetic phenethylamines
 Abstract:
            The synthesis and stereochemical analyses of four isomeric
            2-azabicyclo<2.2.2>octane analogs of mescaline and
            3,4-dimethyloxyphenethylamine are reported.Stereochemical
            assignments were based primarily upon NMR studies employing
            chemical shift reagents.These isomers were evaluated for CNS activity
            utilizing motility response in adapted and non-adapted mice.The
            endo-isomers were found to be more active than the corresponding
            exo-isomers in mimicking the actions of mescaline suggesting that
            mescaline exerts its psychotomimetic effects through an antiperiplanar
            conformation.
 CNR:
            5679875

 Author:
            Wollweber, H.; Hiltmann, R.; Stoepel, K.; Kroneberg, H.-G.
 Reference:
            Journal, EJMCA5, Eur.J.Med.Chem.Chim.Ther., GE, 15, 2, 1980,
            111-118
 Title:
            Stereochemische Untersuchungen ueber Arzneimittel, 8. Mitt.
            1-Phenyl-3-imino-perhydro-3H-oxazolo (3.4-a) pyridine, mit
            blutdrucksteigernder Wirksamkeit
 Abstract:
            New substituted 1-phenyl-3-imino-perhydro-3H-oxazolo
            <3.4-a>pyridines were synthesized by stereospecific cyclisation of
            diastereomeric a-phenyl-2-piperidylmethanols (table 5).These
            compounds and their corresponding unsubstituted configurationally
            isomeric derivatives (tables 1-4) possess hypertensive and
            CNS-stimulating activities dependent on the stereochemistry.The
            pharmacodynamically most interesting derivative, pyriminophen (1)
            has a predominantly central, indirect symphaticomimetic
            activity.Pharmacologically, it may be placed between ephedrine and
            amphetamine. 1 is active by oral administration in patients with arterial
            hypotension and orthostatic disorders.
 CNR:
            5680014

 Author:
            Perrissin, Monique; Luu Duc, Cuong; Narcisse, Guy; Bakri-Logeais,
            Francoise; Huguet, Francois
 Reference:
            Journal, EJMCA5, Eur.J.Med.Chem.Chim.Ther., FR, 15, 6, 1980,
            563-565
 Title:
            Synthese et pharmacologie des derives de l'amino-2 ethoxycarbonyl-3
            phenyl-4 thiophene
 Abstract:
            A series of 3-thiophene carboxylic acid 2-amino 4-phenyl ethyl ester
            has been synthesized.These compounds show a weak
            anti-inflammatory activity but they have a more significant analgesic
            activity.They are CNS minor sedatives.
 CNR:
            5681501

 Author:
            Sharma, Rajendra; Joshi, B.C.; Dua, P.R.
 Reference:
            Journal, PHARAT, Pharmazie, EN, 35, 9, 1980, 542-543
 Title:
            Synthesis and Pharmacological Evaluation of Some 2-N-Alkyl- and
            -Aralkyl-3,4:6,7-dibenzomorphans
 Abstract:
            2-N-Alkyl or 2-aralkyl-5,9-dimethyl-3,4:6,7-dibenzomorphans 3a-c were
            synthesized by condensing 1-alkyl or aralkyl-3,4-dimethylquinolinium
            iodides 1a-c with benzylmagnesium chloride followed by subsequent
            cyclization of 2-benzyl-1-alkyl or aralkyl-3,4-dimethylquinolines
            2a-c.Their structures were established through elemental and spectral
            studies.The preliminary pharmacological screening of 3a-c and other
            3,4:6,7-dibenzomorphans <16> on mice showed that these
            compounds have a depressant action on CNS.
 CNR:
            5690154

 Author:
            Ong, Helen H.; Profitt, James A.; Anderson, V. Brian
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 23, 5, 1980, 494-501
 Title:
            Tricyclics with Analgesic and Antidepressant Activity. 1.
            <<(Alkylamino)ethyl>thio>dibenz<b,f>oxepins and 10,11-Dihydro
            Derivatives
 Abstract:
            A series of <<(alkylamino)ethyl>thio>dibenz<b,f>oxepines (I) and their
            10,11-dihydro derivatives (II) was synthesized and subjected to broad
            analgesic/CNS screening.Several analogues of both types, carrying
            small N-substituents and frequently a nuclear fluorine function, have
            been found to possess potent analgesic activity in the phenylquinone
            writhing assay (PQW) and the tail-flick test in mice.Many of these
            compounds also exhibited significant activity in antagonizing
            tetrabenazine-induced ptosis, as exemplified by 10b, 16b, and
            18b.Results from the mouse jumping test indicated low phisical
            dependence potential for these compounds, and further evidence for a
            nonnarcotic profile was provided by the absence of significant
            naloxone interactions with the tail-flick response.Compound 10b did
            not produce tolerance in mice following chronic administration in the
            PQW screen.
 CNR:
            5697854

 Author:
            Mukerji, D.D.; Nautiyal, S.R.; Prasad, C.R.
 Reference:
            Journal, JPCEAO, J.Prakt.Chem., EN, 322, 5, 1980, 855-858
 Title:
            Synthesis of Some Newly Synthesized Substituted 3-(4'-Aryl
            substituted carbamidoacetyl)aminomethyl-4(3H)quinazolones as CNS
            Depressant Compounds
 Abstract:
 CNR:
            5733066

 Author:
            Hirai, Kentaro; Ishiba, Teruyuki; Sugimoto, Hirohiko; Sasakura,
            Kazayuki; Fujishita, Toshio; et al.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 23, 7, 1980, 764-773
 Title:
            Peptidoaminobenzophenones, a Novel Class of Ring-Opened
            Derivatives of 1,4-Benzodiazepines
 Abstract:
            A series of novel peptidoaminobenzophenones has been prepared via
            several routes and was evaluated for CNS activity.The
            structure-activity relationships in the series are discussed.In general,
            dipeptido-N-Methylaminobenzophenones showed higher activities
            than the corresponding NH derivatives.Some compounds had very
            high activities in antipentylenetetrazole and antifighting tests in mice
            when orally administered.Very weak toxicity was also found in these
            compounds.Water solubility of the peptidoaminobenzophenones and
            their salts were tested.Possible in vivo conversion of
            peptidoaminobenzophenone by enzymatic cleavage of the terminal
            amino acid, followed by chemical cyclization to 1,4-benzodiazepine, is
            also discussed.Such novel open-ring derivatives of
            1,4-benzodiazepine may serve as useful CNS agents.
 CNR:
            5744055

 Author:
            Braun, U.; Shulgin, A. T.; Braun, G.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., GE, 30, 5, 1980, 825-830
 Title:
            Study on the CNS Activity and Analgesia of the N-Substituted Analogs
            of the Amphetamine Derivative
            3,4-Methylenedioxyphenylisopropylamine
 Abstract:
            N-Substituted analogs of 3,4-methylenedioxyphenylisopropylamine
            (MDA) were tested for analgesic potency and influence on motor
            activity in mice following oral administration.These compounds also
            were tested for their psychotomimetic potency in man.Unsubstituted
            MDA and its monoalkyl-homologs with a low number of C-atoms
            (N-methyl-, N-ethyl-MDA) showed both enhancement of motor-activity
            in mice and psychotomimetic effects in man.MDA and N-methyl-MDA
            also showed an analgesic effect which was enhanced by the inclusion
            of a weakly basic group (N-allyl, N-hydroxyethyl).These latter two
            compounds, however, did not influence motor-activity, which makes
            them more recommendable as possible analgesic
            compounds.Structural parallels between these compounds, morphine,
            endorphins and enkephalines, may explain their similar spectrum of
            pharmacological effects. - Key words: Amphetamines; Analgesia;
            Endorphins, enkephalins; 3,4-Methylenedioxyphenylisopropylamine;
            Morphine; Psychotomimetics
 CNR:
            5770403

 Author:
            Spyraki, Ch.; Papaioannou, G.; Tsatsas, G.; Varonos, D.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 30, 3, 1980, 467-470
 Title:
            Pharmacological Activity of New Derivatives of Morphine
 Abstract:
            Three new derivatives of morphine: O3-(b-isopropylaminoethyl) ether
            of morphine (T.3289), O3,O6-<N,N'-bis(methylcarbamate> ester of
            morphine (T.3298) and b-dimethylamino-ethyl-ether of
            dihydromorphinone (T.3403) were tested for their action on CNS.A
            detailed study of pain threshold, motor activity, conditioned behavior
            and noradrenaline levels in brain was carried out.The compounds
            T.3289 and T.3298 exhibited analgesic action.The spontaneous
            activity of rats was decreased by T.3289 and increased by T.3298.The
            conditioned avoidance response was decreased and the brain
            noradrenaline levels were altered. - Key words: Learning; Locomotion;
            Morphine derivatives; Pain
 CNR:
            5793486

 Author:
            Saletu, B.; Gruenberger, J.; Linzmayer, L.; Stadler, R.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 30, 3, 1980, 513-518
 Title:
            Classification and Assessment of Cerebral Bioavailability of Lopirazepam (D-12524) by
            Quantitative EEG and Psychometric Analysis
 Abstract:
            In this double-blind, placebo-controlled study the CNS efficacy and pharmacodynamic
            properties of
            3-hydroxy-5-(o-chlorophenyl)-7-chloro-1,2-dihydro-3H-pyrido<3,2-e>-1,4-diazepin-2-one
            (lopirazepam, D-12524) was investigated in a group of 10 normal
            volunteers.Quantitative EEG and psychometric analyses and clinical evaluations were
            done before as well as 2, 4, 6 and 8 h after oral administration of single doses of
            placebo, 3 mg, 5 mg and 10 mg lopirazepam and 10 mg prazepam.EEG digital
            computer period analysis demonstrated dose-dependent changes, which are typical of
            the class of anxiolytics and which started in the 2nd hour, peaked in the 4th hour and
            lasted after 3 mg, 5 mg and 10 mg up to the 4th, 6th and 8th hour, respectively. 10 mg
            D-12524 produced an additional augmentation of slow waves indicating sleep-inducing
            qualities in this dosage.The equipotent dosage to 10 mg prazepam seems to be 5
            mg.Psychometric analyses demonstrated an improvement in attention, psychomotor
            performance, mood and affectivity after 3 mg, opposite changes after 10 mg
            D-12524.Flickerlight fusion, reaction time, after-image and EAS score were determined
            as well.Data concerning side effects, pulse rate and blood pressure suggested a good
            tolerance of the drug. - Key words: Anxiolytika; D-12524; Lopirazepam; Prazepam
 CNR:
            5793498

 Author:
            Wagner, W.; Ott, H.; Herrmann, W. M.; McDonald, R. J.; Berzewski, B.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 30, 8, 1980, 1240
 Title:
            Contribution to the Human Pharmacological Differentiation of CNS
            Effects of b-Adrenoceptor Blocking Compounds
 Abstract:
 CNR:
            5794198

 Author:
            Jacobi, H.; Dell, H.-D.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., GE, 30, 8a, 1980, 1348-1362
 Title:
            On the Pharmacodynamics of Acemetacin
 Abstract:
            Pharmacodynamic studies were carried out on
            <1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetoxy>acetic acid
            (acemetacin, TV 1322, Rantudil), a new strongly acting non-steroidal
            anti-inflammatory agent for elucidation of its mechanism of
            action.Despite its strong anti-inflammatory activity, acemetacin is only
            a weak inhibitor of prostaglandin release.Release of histamine from
            mast cells induced by N-methylhomoanisylamine-formaldehyde
            condensate (compound 48/80) was strongly inhibited by acemetacin in
            a dose dependent manner.It was also highly effective in in vitro tests,
            for example, in the protein turbidity test of Mizushima.In accordance to
            the weak inhibition of prostaglandin release very little damage was
            done to the mucous membrane of the gastrointestinal tract by this
            anti-inflammatory agent.From these data and from the strong
            anti-inflammatory activity a broad therapeutic margin can be
            derived.Analgetic properties were shown in the benzoquinone test after
            oral and in the Randall-Selitto test after i.m. application.Hyperthermia
            caused by Pyrifer and by yeast is inhibited by acemetacin in a dose
            dependent manner.Corresponding to the weak influence on
            prostaglandin release the reduction of diuresis by acemetacin was
            only small.No tocolytic effect could be detected on the gravid uterus in
            vitro.Function of the heart (isolated heart of guinea-pig) was unaffected,
            but we registered an increase in systolic and diastolic blood pressures
            in the anesthetized dog.Correspondingly, left ventricular pressure also
            increased, these changes were accompanied by bradycardia.Coronary
            flow, peripheral flow and dp/dt did not change, only the pressure in the
            right atrium rose slightly.In cats, acemetacin caused a short-lasting
            decrease in the arterial blood pressure.Effects on CNS were not
            found.Smooth muscles (bronchial/intestinal) were not influenced by
            acemetacin.Like many non-steroidal anti-inflammatory compounds
            acemetacin inhibits also platelet aggregation.Motility of animals was
            lowered.In a granuloma pouch test a strong anti-inflammatory action
            was shown in vivo even without metabolic degradation of
            acemetacin.For the explanation of the anti-inflammatory action several
            mechanisms have to be taken into account. - Key words: Acemetacin,
            pharmacodynamics; Analgesia; Antipyresis; Platelet aggregation
            inhibition; Prostaglandins; Stomach ulcer
 CNR:
            5795374

 Author:
            Iversen, L. L.
 Reference:
            Journal, ARZNAD, Arzneim.Forsch., EN, 30, 5a, 1980, 907-910
 Title:
            The Present Status of Benzodiazepines in Psychopharmacology
 Abstract:
            The benzodizepines cintinue to offer many challenging questions for
            the pharmacologist.For example, do the various different properties
            exhibited by benzodiazepines, notably the sedative, anxiolytic and
            anticonvulsant effects, reflect aspects of a single common mechanism
            of action, or are these properties dissociable? To what extent do
            chemically unrelated drugs with similar CNS actions, such as the
            barbiturates, share a common mechanism of action with the
            benzodiazepines? The development of biochemical techniques for
            identifying and characterizing CNS benzodiazepine receptors by
            radioligand binding in vitro and in vivo has been an important recent
            advance, although the benzodiazepine receptor remains in many ways
            an enigma.The hypothesis that the anticonvulsant actions of these
            drugs may be due to their ability to enhance the actions of GABA at
            CNS synapses is an attractive one, but many questions remain: Do all
            CNS benzodiazepine receptors interact with GABA sites, and are all
            GABA receptors linked to benzodiazepine sites? What is the
            endogenous ligand for the benzodiazepine receptors? Can the
            anxiolytic and sedative effects of the benzodiazepines be explained by
            their interaction with GABA mechanisms, or are other interactions more
            important? Is there more than one sub-type of benzodiazepine receptor
            in brain? Although these questions cannot be unequivocally answered,
            the benzodiazepines currently represent one of the most active and
            exciting areas for basic psychopharmacological research. - Key words:
            Benzodiazepines, basic research * GABA receptors *
            Psychopharmacology
 CNR:
            5796047

 Author:
            Ellis, K. O.; Schwan, T. J.; Wessels, F. L.; Miles, N. J.
 Reference:
            Journal, JPMSAE, J.Pharm.Sci., EN, 69, 10, 1980, 1194-1198
 Title:
            1-(Substituted benzyl)-3,4,5,6-tetrahydro-2(1H)-pyrimidones: A Series
            with Stimulant and Depressant Activities
 Abstract:
            A series of 1-(substituted benzyl)-3,4,5,6-tetrahydro-2(1H)-pyrimidones
            was synthesized by catalytic hydrogenation of the corresponding
            1-(substituted benzyl)-2(1H)-pyrimidone.The pharmacological
            evaluation of these compounds in mice revealed a unique profile that
            included evidence of CNS stinulation and depression within the series
            and in the same compounds.Some members of this series induced
            signs of only CNS stimulation, some compounds caused signs of only
            CNS depression and skeletal muscle relaxation, and some caused
            signs of both stimulation and depression in the same animal.This
            apparent dual activity was assessed further in mice antidepressant
            tests based on tetrabenazine antagonism and with
            antianxiety/anticonvulsant tests on the antagonism of a number of
            convulsants.The 4-chloro-, 4-fluoro-, 4-bromo-, and 3,4-dichlorobenzyl
            compounds exhibited antidepressant and antianxiety activities in the
            same dose range.Among these four compounds, the
            3,4-dichlorobenzyl compound possessed the lowest antitetrabenazine
            (17 mg/kg po) and antipentylenetetrazol (23 mg/kg po) ED50
            values.The 4-fluoro compound antagonized tetrabenazine-,
            pentylenetetrazol-, and isoniazid-induced tonic convulsions in the
            same dose range (ca. 50 mg/kg po).
 CNR:
            5799091

 Author:
            Cannon, Joseph G.; Lee, Teresa; Goldman, H. Duane; Long, John
            Paul; Flynn, Jan R.; et al.
 Reference:
            Journal, JMCMAR, J.Med.Chem., EN, 23, 1, 1980, 1-5
 Title:
            Congeners of the b Conformer of Dopamine Derived from cis- and
            trans-Octahydrobenzo<f>quinoline and
            trans-Octahydrobenzo<g>quinoline
 Abstract:
            The so-called b conformer of dopamine has been proposed to be
            involved in agonist-receptor interactions at several sites in the
            dopaminergic nervous system.Further to evaluate this proposal, rigid
            congeners of the b conformer derived from linearly and angularly
            annelated octahydrobenzoquinolines have been synthesized.Certain
            N-alkylated trans-angularly annelated systems exhibited unusually
            potent and highly selective dopamine-like effects in an assay on a
            cardioaccelerator nerve preparation in the cat, but these compounds
            were inactive in variety of assays for CNS effects.These compounds
            present a clear separation of CNS effects from some potent peripheral
            effects.
 CNR:
            5804330

 Author:
            Tiwari, S. S.; Agarwal, Rajesh; Satsangi, R. K.
 Reference:
            Journal, JICSAH, J.Indian Chem.Soc., EN, 57, 10, 1980, 1040-1042
 Title:
            Synthesis and CNS Activity of
            1-(5'-Alkyl,1',3',4'-thiadiazol-2'-yl),2-methyl,4-arylidene-imidazol-5-ones
 Abstract:
 CNR:
            5860260

 Author:
            Calvino, R.; Mortarini, V.; Serafino, A.
 Reference:
            Journal, FRPSAX, Farmaco Ed.Sci., IT, 35, 3, 1980, 240-247
 Title:
            STUDIO DI ALCUNI DERIVATI DEL NUCLEO BENZOTRIAZOLICO
 Abstract:
            The syntheses of 1-(b-dimethylaminoethoxy)benzotriazole,
            1-(g-dimethylaminopropoxy)benzotriazole and of their N-oxide isomers
            3-(b-dimethylaminoethyl)benzotriazole 1-oxide and
            3-(g-dimethylaminopropyl)benzotriazole 1-oxide are reported.The
            structure of these compounds has been confirmed by N.M.R.
            spectroscopy; the structures of the N-oxide derivatives was also
            elucidated by chemical reduction to the parent benzotriazoles.The two
            benzotriazoles were also tested for antiinflammatory activity in the rat,
            and for analgesic and depressant activity on the CNS of the mouse.
 CNR:
            5879841

 Author:
            Joshi, Krishna C.; Pathak, Vijai N.; Chand, Pooran
 Reference:
            Journal, JICSAH, J.Indian Chem.Soc., EN, 57, 1980, 423-425
 Title:
            Possible Psychopharmacological Agents, Part XI : Synthesis and CNS
            Activity of Some Fluorine Containing Indole Derivatives
 Abstract:
            2-(4'-Fluorophenyl)indole undergoes Mannich reaction with
            1-arylpiperazines and formaldehyde (40percent) to give the
            corresponding 3-(1-arylpiperazinomethyl)-2-(4'-fluorophenyl)indoles.
            3-Chloroacetyl-2-(4'-fluorophenyl)indole produces
            3-(1-arylpiperazinoacetyl)-2-(4'-fluorophenyl)indoles by the reaction of
            the corresponding 1-arylpiperazines.All the compounds have been
            characterized by IR, PMR and 19F NMR spectral studies.Some
            compounds have been screened for CNS activity on different
            parameters.
 CNR:
            5880756

 Author:
            Shukla, J. S.; Ahmad, I.
 Reference:
            Journal, JICSAH, J.Indian Chem.Soc., EN, 57, 1980, 950-953
 Title:
            Studies on Biologically Active Agents: Synthesis of Variously
            Substituted N1-(4-substituted phenoxy acetyl/benzoyl secondary
            amines)-N2-Substituted Aryl Thioureas as Possible CNS,
            Anticonvulsant and MAO Inhibitory Agents
 Abstract:
 CNR:
            5881116
