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Subtype selective y-Aminobutyric acid type A receptor (GABAAR) modulators acting at the benzodiazepine binding site: An update

Maramai, Samuele, Benchekroun, Mohamed, Ward, Simon E. and Atack, John R. 2020. Subtype selective y-Aminobutyric acid type A receptor (GABAAR) modulators acting at the benzodiazepine binding site: An update. Journal of Medicinal Chemistry 63 (7) , pp. 3425-3446. 10.1021/acs.jmedchem.9b01312

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Abstract

γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter within the central nervous system (CNS) with fast, transsynaptic, and modulatory extrasynaptic effects being mediated by the ionotropic GABA type A receptors (GABAARs). These receptors are of particular interest because they are the molecular target of a number of pharmacological agents, of which the benzodiazepines (BZDs), such as diazepam, are the best described. The anxiolytic, sedating, and myorelaxant effects of BZDs are mediated by separate populations of GABAARs containing either α1, α2, α3, or α5 subunits and the molecular dissection of the pharmacology of BZDs indicates that subtype-selective GABAAR modulators will have novel pharmacological profiles. This is best exemplified by α2/α3-GABAAR positive allosteric modulators (PAMs) and α5-GABAAR negative allosteric modulators (NAMs), which were originally developed as nonsedating anxiolytics and cognition enhancers, respectively. This review aims to summarize the current state of the field of subtype-selective GABAAR modulators acting via the BZD binding site and their potential clinical indications.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: ACS Publications
ISSN: 0022-2623
Date of First Compliant Deposit: 2 January 2020
Date of Acceptance: 18 November 2019
Last Modified: 18 Nov 2020 03:05
URI: http://orca-mwe.cf.ac.uk/id/eprint/128150

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