title: 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.
authors.affiliation: Adrien Albert Laboratory of Medicinal Chemistry, Department of Pharmacology, University of Sydney, New South Wales, Australia.
authors.forename: G A
authors.initials: GA
authors.lastname: Johnston
mesh_terms: D000085:Acetates / Q000737:chemistry / Q000494:pharmacology; D000179:Acrylates / Q000737:chemistry / Q000494:pharmacology; D000588:Amines; D000700:Analgesics / Q000494:pharmacology; D000871:Anthelmintics / Q000494:pharmacology; D000927:Anticonvulsants / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology; D003198:Computer Simulation; D003509:Cyclohexanecarboxylic Acids; D003517:Cyclopentanes / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D000077206:Gabapentin; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology; D008968:Molecular Conformation; D008970:Molecular Weight; D011963:Receptors, GABA-A / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D000085:Acetates; D000179:Acrylates; D000588:Amines; D000700:Analgesics; D000871:Anthelmintics; D000927:Anticonvulsants; D003509:Cyclohexanecarboxylic Acids; D003517:Cyclopentanes; D007555:Isoxazoles; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; C075501:3-aminocyclopentane-1-carboxylic acid; D000077206:Gabapentin; C058552:3-((aminoiminomethyl)thio)-2-propenoic acid; C015542:gaboxadol; D001640:Bicuculline