Ionotropic GABA Receptors as Therapeutic Targets for Memory and Sleep Disorders Mary Chebib, 1 Jane R. Hanrahan, 1 Kenneth N. Mewett, 2 Rujee K. Duke, 1,2 and Graham A. R. Johnston 2 1 Faculty of Pharmacy, The Adrien Albert Laboratory of Medicinal Chemistry, The University of Sydney, Sydney, NSW 2006, Australia 2 Department of Pharmacology, The Adrien Albert Laboratory of Medicinal Chemistry, The University of Sydney, Sydney, NSW 2006, Australia Contents 1. Introduction 13 2. Ionotropic GABA receptors 14 2.1. Molecular composition of ionotropic receptors 15 2.2. GABA A and GABA C receptor pharmacology 15 2.3. Modulators of ionotropic GABA receptors 16 3. Ionotropic GABA receptors and sleep disorders 16 4. Ionotropic GABA receptors and memory disorders 19 5. Conclusion 21 References 21 1. INTRODUCTION The chemical diversity of agents acting on receptors for g-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain, is substantial and increasing. This rich diversity offers both challenges and opportunities for medicinal chemists [1]. GABA produces neuronal inhibition by acting on two major types of receptors: ionotropic receptors that are ligand-gated ion channels (GABA A and GABA C receptors) [1], and metabotropic receptors that are G-protein coupled receptors (GABA B receptors) that act via second messengers [2]. The ionotropic GABA A and GABA C receptors belong to the nicotinicoid superfamily of ligand-gated ion channels that includes nicotinic acetyl- choline, strychnine-sensitive glycine and 5HT 3 receptors [3]. Although GABA C receptors are sometimes classified as subtypes of GABA A receptors, they differ in their ability to form endogenous heteromeric and homomeric receptors respectively, and in their physiological and pharmacological properties [4]. There is also a significant diversity of ionotropic GABA receptor subtypes composed of different protein subunits. The discovery of subtype specific agents is a major challenge in the continuing development of ionotropic GABA receptor pharmacology. Leads for the discovery of new chemical entities that selectively influence ionotropic GABA receptors come from using recombinant receptors of known subunit composition and the use of genetically modified mice [5]. This has been elegantly demonstrated in ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOLUME 39 q 2004 Elsevier Inc. ISSN: 0065-7743 DOI 10.1016/S0065-7743(04)39002-0 All rights reserved