title: A novel benzodiazepine inverse agonist, S-8510, as a cognitive enhancer.
abstract: 1. Pharmacological actions of a novel benzodiazepine receptor ligand, S-8510 (2-(3-isoxazolyl)-3,6,7,9-tetrahydroimidazo[4,5-d]pyrano+ ++[4,3-b] pyridine monophosphate monohydrate), were examined in in vitro and in vivo studies. 2. S-8510 was characterized as a partial inverse agonist with a modest GABA ratio and low efficacy. 3. S-8510 ameliorated memory impairment induced by cholinergic deficit in the water maze paradigm of Wistar rats. 4. S-8510 augmented LTP of the Schaffer collateral/commissural fiber-CA1 synapses in the hippocampal slice preparations of SD rat. 5. S-8510 increased the extracellular levels of acetylcholine and noradrenaline in the hippocampus of Wistar rat. 6. S-8510 selectively potentiated pentylenetetrazol-induced convulsion without affecting minimal electroconvulsive shock- or strychnine-induced convulsion in ddY mice. 7. S-8510 failed to induce any sign of anxiety in the Wistar rat pro-conflict test. 8. S-8510 showed antidepressant-like pharmacological actions in ddY mice. 9. These results suggest that S-8510 can be used as a therapeutic drug for senile dementia, including Alzheimer's disease with little risk for inducing anxiety or convulsion.
authors.affiliation: Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kawasaki
authors.forename: M
authors.initials: M
authors.lastname: Eigyo
authors.forename: M
authors.initials: M
authors.lastname: Ikeda
authors.forename: T
authors.initials: T
authors.lastname: Kihara
authors.forename: K
authors.initials: K
authors.lastname: Koike
authors.forename: A
authors.initials: A
authors.lastname: Matsushita
authors.forename: S
authors.initials: S
authors.lastname: Murata
authors.forename: T
authors.initials: T
authors.lastname: Shiomi
authors.forename: S
authors.initials: S
authors.lastname: Takada
authors.forename: M
authors.initials: M
authors.lastname: Yasui
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001007:Anxiety / Q000139:chemically induced / Q000523:psychology; D001569:Benzodiazepines / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D018697:Nootropic Agents / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology; D013268:Stimulation, Chemical
chemical_list: D014151:Anti-Anxiety Agents; D018697:Nootropic Agents; C105893:S 8510; D001569:Benzodiazepines