title: Ro 15-4513: partial inverse agonism at the BZR and interaction with ethanol.
abstract: The imidazobenzodiazepinone derivative Ro 15-4513 has the activity profile of a partial inverse (low efficacy) agonist at the benzodiazepine receptor (BZR). It reverses central nervous depressant effects of diazepam, and, in part, of phenobarbitone and ethanol in mice, rats and cats in behavioural, electrophysiological, and neurochemical paradigms. The interaction of Ro 15-4513 with barbiturates and ethanol is due to its inverse agonistic (negative allosteric modulatory) property at the BZR, as it was reversed by the selective BZR blocker flumazenil (Ro 15-1788). In the present experiment situations, other BZR partial inverse agonists in subconvulsant or overt convulsant doses were less effective against ethanol effects than Ro 15-4513. Possible mechanisms for this differential activity of BZR inverse agonists are discussed.
authors.affiliation: Pharmaceutical Research Department, F. Hoffmann-La Roche & Co., Ltd., Basel, Switzerland.
authors.forename: E P
authors.initials: EP
authors.lastname: Bonetti
authors.forename: W P
authors.initials: WP
authors.lastname: Burkard
authors.forename: M
authors.initials: M
authors.lastname: Gabl
authors.forename: W
authors.initials: W
authors.lastname: Hunkeler
authors.forename: H P
authors.initials: HP
authors.lastname: Lorez
authors.forename: J R
authors.initials: JR
authors.lastname: Martin
authors.forename: H
authors.initials: H
authors.lastname: Moehler
authors.forename: W
authors.initials: W
authors.lastname: Osterrieder
authors.forename: L
authors.initials: L
authors.lastname: Pieri
authors.forename: P
authors.initials: P
authors.lastname: Polc
mesh_terms: D000818:Animals; D001386:Azides / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001569:Benzodiazepines / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D001923:Brain Chemistry / Q000187:drug effects*; D002415:Cats; D003975:Diazepam / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004594:Electrophysiology; D000431:Ethanol / Q000494:pharmacology*; D005442:Flumazenil / Q000494:pharmacology; D015201:Meta-Analysis as Topic; D051379:Mice; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects*
chemical_list: D001386:Azides; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D000431:Ethanol; D005442:Flumazenil; C042957:Ro 15-4513; D003975:Diazepam; D010634:Phenobarbital