Characterization of the GABAA Receptor Recognition Site Through Ligand Design and Pharmacophore Modeling

4-Aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian central nervous system (CNS), mediates its actions through the ionotropic GABAA and GABAC receptors and the metabotropic GABAB receptors. This classification of the GABA receptors has been developed over a period of 40 years and is primarily based on the pharmacology of a limited number of selective ligands (1). GABA primarily acts through GABAA receptors, which are built as pentameric assemblies of different families of receptor subunits. Although a large number of subunits have been identified, only a limited number of physiological GABAA receptors are believed to exist. In addition to the recognition site for GABA, the existence of several modulatory sites for a number of therapeutic agents, including benzodiazepines, barbiturates, neurosteroids, and volatile anaesthetics adds to the complexity of the GABAA receptor system (2).