Besides playing an important role in central neurotransmission processes, GABAA receptors have been implied in a number of neurological and psychiatric disorders. These observations have focused interest on the molecular mechanisms of receptor activation and the structural basis of receptor-ligand interaction. To study the structural requirements for receptor-ligand interaction, different areas in the ligand-binding site of the GABAA receptor have been evaluated by development and application of a 3-D pharmacophore model based on a number of known GABAA agonists. During this study, a series of highly potent and selective GABAA antagonists, based on the structure of the partial GABAA agonist 5-(4-piperidyl)-3-isoxazolol (4-PIOL), has been developed. These results demonstrate the presence of a receptor pocket of considerable dimensions containing specific sites for receptor interactions in the vicinity of the 4-position of the 3-isoxazolol ring in 4-PIOL.