GABAA agonists as targets for drug development

Abstract

1. Agents with selective actions on bicuculline-sensitive GABAA receptors have been developed by systematically restricting the conformational mobility of the GABA molecule. 2. THIP, a bicyclic isoxazole that represents GABA held in a relatively rigid and partially extended conformation, is an analgesic of potency comparable to that of morphine. THIP represents a lead compound for a novel series of analgesics acting independently of Naloxone-sensitive opiate systems. 3. ZAPA, a conformationally-restricted analogue of GABA containing an isothiouronium moiety, is a selective agonist for low affinity GABAA receptors and is a lead compound for the development of a novel series of anthelmintics. 4. (+)-TACP, a cyclopentane analogue of GABA, may activate a different subclass of GABAA receptors from THIP. 5. Pharmacological, molecular modelling and molecular biological studies provide evidence for a heterogeneity of GABAA receptors which might be exploited for drug development.