title: The novel anxiolytic U-101017: in vitro and ex vivo binding profile and effect on cerebellar cGMP.
abstract: The binding affinities (Ki) of U-101017 and diazepam for the GABA(A) receptor in rat cortical membranes were determined using [3H]flunitrazepam ([3H]FNZ) as the ligand. The inhibition constants of U-101017 and diazepam were 3.78 nM and 6.36 nM, respectively. Brain uptake of U-101017 was studied by the ex vivo [3H]FNZ binding assay. A significant ex vivo inhibition of [3H]FNZ binding was observed 10 min after oral administration of U-101017, and the effect lasted for at least 240 min (the last time point of investigation). The potential anxiolytic activity of U-101017 and diazepam was investigated in nonstressed and stressed (electric foot shock) mice by quantitative estimation of cerebellar cyclic 3',5'-guanosine monophosphate (cGMP). Both U-101017 and diazepam dose-dependently decreased cGMP and attenuated stress-induced elevations in cGMP. These effects were antagonized by the GABA(A) receptor antagonist flumazenil. U-101017 was about two orders of magnitude more potent in stressed animals than in controls. The results of our investigation indicate that the anxiolytic-like activity of U-101017 is mediated via GABA(A) receptors.
authors.affiliation: CNS Research, Pharmacia & Upjohn, Inc., Kalamazoo, MI 49001, USA.
authors.forename: V H
authors.initials: VH
authors.lastname: Sethy
authors.forename: H
authors.initials: H
authors.lastname: Wu
mesh_terms: D000818:Animals; D001665:Binding Sites; D002531:Cerebellum / Q000187:drug effects* / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D011804:Quinolines / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C104547:7-chloro-5((cis-3,5-dimethylpiperazine)carbonyl)imidazo(1,5a)quinoline-3-carboxylate; D018696:Neuroprotective Agents; D011804:Quinolines; D006152:Cyclic GMP