30Th Annual Meeting of Society for Neuroscience. New Drugs Affecting the Central Nervous System New Orleans, Louisiana, USA November 4–9, 2000
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CNS Drug Reviews Vol. 7, No. 2, pp. 241–248 © 2001 Neva Press, Branford, Connecticut MEETING REPORT 30th Annual Meeting of Society for Neuroscience. New Drugs Affecting the Central Nervous System New Orleans, Louisiana, USA November 4–9, 2000 Alexander Scriabine Yale University School of Medicine, New Haven, CT, USA The 30th meeting of the Society for Neuroscience was held on November 4–9 in New Orleans, LA, USA. The meeting was attended by ~25,000 scientists and exhibitors. There were 874 slide or poster sessions, symposia or special lectures. Each session contained 10 to 20 presentations. This report covers only selected posters on new drugs affecting the central nervous system. NEUROPROTECTIVE DRUGS M. Cheng et al. (Centaur Pharmaceuticals, Inc., Sunnyvale, CA, USA) presented NXY-50, a novel free radical trapping agent, that was found to reduce infarct volume in rats with permanent focal ischemia induced by occlusion of middle cerebral artery (MCAO). The drug (30 or 60 mg/kg) was administered at 5 min after MCAO by i.v. bolus followed by infusion for 24 h (same dose per hour). The animals were sacrificed at 24 h after MCAO. The infarct volumes were estimated by histochemical staining. At 60 mg/kg the effect of the drug was statistically significant. J. Peeling et al. (Univ. of Mannitoba, Winnipeg, Canada, Memorial Univ., St. John’s, Newfoundland, Canada and AstraZeneca, Loughborough, UK and Södertalje, Sweden) studied NXY-059 in a rat model of hemorrhagic stroke. Intracerebral hemorrhage (ICH) was induced in rats by infusion of collagenase into SO Na 3 the right caudate nucleus. NXY-059 was adminis- tered s.c. at 30 min after ICH induction, at 50 N+ mg/kg s.c., followed by infusion at 8.8 mg/kg/h. – O MR imaging was performed at 1, 7, and 42 days NaO S 3 after ICH induction. Neurological deficits were es- NXY-059 timated by beam walking, circling, posture reflex Address correspondence to: Dr. A. Scriabine, Department of Pharmacology, Yale University School of Med- icine, 333 Cedar Street, New Haven, CT 06520 USA. Fax: +1 (203) 458-8428. E-mail: [email protected] 241 242 A. SCRIABINE and forelimb use. NXY-059 had no effect on the size of hematoma, but significantly re- duced neurological deficits. V. Lavie et al. and A. Bar-Joseph et al. OH (Pharmos Ltd., Kyriat Weizmann, Rehovot, Israel) studied neuroprotective effects of dexana- OH binol (HU-211) in rats. Dexanabinol is a synthe- tic non-psychotropic cannabinoid with NMDA- antagonist, antioxidant and antiinflammatory properties. At 5 mg/kg i.v. dexanabinol reduced CH3 infarct size and improved functional outcome in HC3 the rat transient MCAO model. When adminis- HC CH3 3 HC tered at the end of occlusion period (90 min) de- 3 xanabinol reduced mortality rate and prevented Dexanabinol (HU-211) MCAO-induced reduction in body weight gain. Dexanabinol was recently reported to benefit pa- tients with severe head trauma. T. Müller et al. (Bayer AG, Wuppertal and Leverkusen, Germany and CNRS UPR-9023, Montpellier, France) found that BAY 36-7620, a selective metabotropic glu- tamate receptor 1 (mGluR1) antagonist, is neuroprotective in the rat MCAO model at 3 ´ 0.03 to 3.0 mg/kg i.v. (at 0, 2, and 4 h post occlusion) and in the rat acute subdural hematoma model at 0.01 mg/kg/h for 4 h after surgery. At neuroprotective doses BAY 36-7620 had no phencyclidine-like adverse effects (see poster by A. G. Chapman, below, for the structure and anticonvulsant activity of BAY 36-7620). A. Bodner et al. (Univ. of Chicago, Chicago, IL, USA) described neuroprotective ef- fects of CEP-1347/KT7515, an inhibitor in JNK signalling pathway, in rat dorsal root ganglion (DRG) neurons. At 200 nM CEP-1347/KT7515 protected DRGs from neuro- toxicity induced by GP120IIIB. This drug is a novel anti-apoptotic agent that can possibly be useful in the prevention of AIDS neuropathy. N O CH32 CH SCH 2 CH223 SCH CH N N O HO CO23 CH CEP-1347/KT7515 MEMORY AND LEARNING ENHANCING DRUGS F. A. Guarraci et al. (Univ. of Vermont, Burlington, VT, USA) studied the effects of a cannabinoid (CB1) agonist, SR 141 716 and of cannabinoid (CB1) antagonist, HU-210 on CNS Drug Reviews, Vol. 7, No. 2, 2001 DRUGS AFFECTING CNS 243 Pavlovian fear conditioning in rats. The authors concluded that CB1 antagonist enhances memory formation, while CB1 agonist impairs memory formation. O HC3 N N H CH OH N 2 N OH Cl Cl O Cl SR 141 716 HU-210 T. Sumiyoshi et al. (Toyama Medical Univ., Toyama, Japan and Vanderbilt Univ., Nashville, TN, USA) studied the effects of tandospirone, a 5-HT1A agonist, on memory function in schizophrenic patients. Tandospirone was administered at 30 mg/day, for 4 weeks to 11 patients. The drug significantly improved Verbal and General Memory com- posites in the Wechsler Memory Scale — Revised (WMS-R). A. M. Smith and J. M. Wehner (Univ. of O O Colorado, Boulder, CO, USA) demonstrated that aniracetam (100 mg/kg) improves contextual C / N learning in DBA 2 mice. This effect was asso- ciated with an increase in brain g-protein kinase HCO C (PKC). Aniracetam and oxiracetam were pre- 3 viously described to have similar effects. Aniracetam T. M. Abouelleil et al. (Univ. of California at Los Angeles, CA, USA) studied genes that are likely to determine behavior of mice in the Morris water maze. They compared expression of various genes in the hippocampus of two strains of mice: C57/BL6J (capable of learning the maze) and 129/SvJ (incapable of learning). The expression of some genes in these two strains of mice differed substantially. CD81 antigen was almost 5-fold higher expressed in C57/Bl6J mice. NMDA RECEPTOR ANTAGONISTS New NMDA antagonists appear to have many different indications in the treatment of CNS disorders. The new selective NMDA 1A/2B receptor antagonist from Pfizer, CI-1041 (PD 0196860) was shown to be potentially useful as an antiparkinsonian, anal- gesic and anticonvulsant drug. K. A. Serpa et al. and C. L. Christoffersen et al. (Pfizer, Ann Arbor, MI, USA) described antiparkinsonian effects of CI-1041. At 3 or 10 mg/kg p.o. CI-1041 potentiated L-DOPA- or quinpirole-induced contraversive rotations in 6- OHDA-lesioned rats. This effect was still present after 9 days of repeated administration. In MLTP-treated monkeys CI-1041did not alter the antiparkinsonian effect of half of a CNS Drug Reviews, Vol. 7, No. 2, 2001 244 A. SCRIABINE normal dose of L-DOPA, but reduced L-DOPA-induced dyskinesias and enhanced L- DOPA-induced contraversive rotations. J. A. Fillard et al. (Pfizer, Ann Arbor, MI, USA) studied analgesic effects of CI-1041. At3to30mg/kg p.o. CI-1041 inhibited early and late phases of the formalin effect in the formalin foot pad test in rats. It was ineffective in the acetic acid-induced writhing test in mice. M. G. Vartanian et al. (Pfizer, Ann Arbor, MI, USA) presented the anticonvulsant profile of CI-1041. Maximal electroshock-induced seizures in rats were partially antago- nized by CI-1041 (60% protection at 50 mg/kg p.o.). Audiogenic seizures in DBA/2 mice / / were completely blocked by CI-1041 (ED50 = 6.3 mg kg p.o.). At 10 mg kg p.o. CI-1041 protected rats from corneal induced kindled seizures. No adverse behavioral effects were observed. N O N FSO O CI-1041 (PD 0196860) ANTIPSYCHOTICS B. Pouzet et al. (H. Lundbeck A/S, Valby, Denmark) studied pharmacology of SB- 258741 [R-(+)-1-(toluene-3-sulfonyl)-2-{2-(4-methylpiperidin-1-yl)ethyl}-pyrrolidine], a m / 5-HT7 receptor antagonist, in rats. At 26 mol kg s.c. SB 258741 reversed phencyclidine (PCP)-disrupted, but had no effect on amphetamine-disrupted pre-pulse inhibition (PPI). It reduced spontaneous motor activity and amphetamine-induced hyperactivity, reduced spontaneous and PCP-disrupted social interaction, but did not affect startle amplitude. The authors concluded that SB-258741 is not likely to have antipsychotic activity in humans. T. Morimoto et al. and Y. Shiigi et al. (Welfide Corporation, Iruma, Saitama, Japan) presented Y-931 {8-fluoro-12(4-methylpiperazin-1-yl)-6 H-[1]benzothieno[2,3-b][1,5] benzodiazepine maleate}, a novel antypsychotic. Its interaction pattern with neurotrans- mitters was similar to that of clozapine; it did not cause catalepsy, but antagonized MK- 801-induced vacuolization and social deficits. Y-931 caused expression of fos-protein in mesolimbic areas and transiently increased plasma prolactin. X. Guitart et al. (Centro De Investigacion, Barcelona, Spain) studied the effects of E-5842, a sigma-1 receptor ligand and potential atypical antipsychotic, on gene expression in the brain of rats. The drug was administered to rats at 20 mg/kg/day for 21 days. Ex- pression of various genes was changed by drug treatment. The major regulated gene was fibroblast growth factor (FGF). N CO2 H F N N HO CO2 H N CO2 H E-5842 CNS Drug Reviews, Vol. 7, No. 2, 2001 DRUGS AFFECTING CNS 245 ANTI-ALZHEIMER DRUGS N W. Gaida and M. Wienrich (Boehringer Ingelheim CH / GmbH, Ingelheim Rhein, Germany) studied M1 receptor O agonists: talsaclidine and sabcomeline on EEG of rabbits. Sabcomeline [(R)-3-quinuclidineglyoxilonitrile (Z)–O–me- H thyloxime], at 0.003 and 0.01 mg/kg s.c., and talsaclidine, Talsaclidine at3to30mg/kg s.c., increased theta power and decreased alpha power. At effective doses sabcomeline produced cho- linergic side effects (diarrhea and salivation), while talsacli- dine showed a clear separation between therapeutic and adverse effects; it was effective at 3mg/kg but produced side effects only at 30 mg/kg.