Ro 15-4513: Partial inverse agonism at the BZR and interaction with ethanol

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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.

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    Abstracts of part of this work have been presented at the Eighth European Neuroscience Congress, the Hague, The Netherlands, September 11th–15th, 1984, at the Summer Meeting of the British Pharmacological Society, Southamptom, U.K., July 17th–19th, 1985, and at the 17th Annual Meeting of the Society for Neuroscience, New Orleans, LA, November 15th, 1987, at the Symposium “Antagonizing the behavioral effects of ethanol using drugs that act at the benzodiazepine/GABA receptor macromolecular complex.”

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