title: Neuropharmacological profile of a novel potential atypical antipsychotic drug Y-931 (8-fluoro-12-(4-methylpiperazin-1-yl)- 6H-[1]benzothieno[2,3-b][1,5] benzodiazepine maleate).
abstract: The neuropharmacological profile of Y-931, 8-fluoro-12- (4-methylpiperazin-1-yl)- 6H-[1]benzothieno [2,3-b][1,5]benzodiazepine maleate, was investigated in comparison with those of typical and claimed atypical antipsychotic drugs. Similar to clozapine and olanzapine, Y-931 interacted with multiple neurotransmitter receptors such as dopaminergic, serotonergic, alpha-adrenergic, muscarinic and histaminergic receptors. Y-931, as well as the other antipsychotics, was active in a dose-dependent manner in established tests which are indicative of potential antipsychotic activity such as inhibition of apomorphine-induced hyperactivity and suppression of conditioned avoidance responses, however, only Y-931 and clozapine were devoid of cataleptogenic potential. In models of N-methyl-D-aspartate (NMDA) receptor hypofunction, Y-931 demonstrated the most potent protective action against the dizocilpine-induced neurotoxicity (neuronal vacuolization) in the rat retrosplenial cortex ([Y-931 (ED(50); 0.20 mg/kg, p.o.), olanzapine (1.1), clozapine (5.7), risperidone (6.9), haloperidol (19)). Furthermore, Y-931 and clozapine, unlike the other antipsychotics used, reversed the dizocilpine-induced social deficits at the same doses at which their neuroprotective action was exhibited. The present results suggest that Y-931 may be a novel potential atypical antipsychotic drug with a low risk of extrapyramidal syndrome (EPS) and the property to ameliorate NMDA receptor hypofunction.
authors.affiliation: Drug Discovery Laboratories, Pharmaceutical Research Division, Welfide Corporation 7-25, Koyata 3-Chome, Iruma, Saitama 358-0026, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Morimoto
authors.forename: Kenji
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yasumatsu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tanaka
authors.forename: Masatake
authors.initials: M
authors.lastname: Fujimura
authors.forename: Makoto
authors.initials: M
authors.lastname: Kuriyama
authors.forename: Koreichi
authors.initials: K
authors.lastname: Kimura
authors.forename: Shuzo
authors.initials: S
authors.lastname: Takehara
authors.forename: Keiji
authors.initials: K
authors.lastname: Yamagami
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001058:Apomorphine / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects; D001569:Benzodiazepines / Q000494:pharmacology*; D002375:Catalepsy / Q000139:chemically induced / Q000523:psychology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists; D017981:Receptors, Neurotransmitter / Q000187:drug effects; D012919:Social Behavior
chemical_list: C434584:8-fluoro-12-(4-methylpiperazin-1-yl)-6H-(1)benzothieno(2,3-b)(1,5)benzodiazepine; D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D018691:Excitatory Amino Acid Antagonists; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D001569:Benzodiazepines; D016291:Dizocilpine Maleate; D001058:Apomorphine