γ-Aminobutyric acid (GABA) is the major inhibitory transmitter controlling synaptic transmission and neuronal excitability. It is present in a high percentage of neurons in the central nervous system (CNS) and also present in the peripheral nervous system, and acts to maintain a balance between excitation and inhibition. GABA acts via three subclasses of receptors termed GABAA, GABAB, and GABAC. GABAA and GABAC receptors are ligand-gated ion channels, while GABAB receptors are G-protein coupled receptors. Each class of GABA receptor has distinct pharmacology and physiology. GABAA receptors are heteropentameric transmembrane protein complexes made up of α1-6, β1-3, γ1-3, δ, ε, θ, π subunits, giving rise to numerous allosteric binding sites and have thus attracted much attention targets for the treatment of conditions such as epilepsy, anxiety and sleep disorders. The development of ligands for these binding sites has also led to an improved understanding of the different physiological functions and pathological processes and offers the opportunity for the development of novel therapeutics. This review focuses on the medicinal chemistry aspects including drug design, structure-activity relationships (SAR), and mechanism of actions of GABA modulators, including non-benzodiazepine ligands at the benzodiazepine binding site and modulators acting at sites other than the high-affinity benzodiazepine binding site. Recent advances in this area their future applications and potential therapeutic effects are also highlighted.
Keywords: Drug design and development; GABA(A) allosteric modulators; Structure-activity relationships; Therapeutic agents.
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