The GABA _A receptor system is implicated in a number of central nervous system (CNS) disorders, making GABA _A receptor ligands interesting as potential therapeutic agents. Only a few different classes of structures are currently known as ligands for the GABA recognition site on the hetero-pentameric GABA _A receptor complex, reflecting the very strict structural requirements for GABA _A receptor recognition and activation. A large number of the compounds showing agonist activity at the GABA _A receptor site are structurally derived from the GABA _A agonists muscimol, THIP (Gaboxadol), or isoguvacine, which we developed at the initial stage of the project. Using recombinant GABA _A receptors, functional selectivity has been shown for a number of compounds, including THIP, showing subunit-dependent potency and maximal response. The pharmacological and clinical activities of THIP probably reflect its potent effects at extrasynaptic GABA _A receptors insensitive to benzodiazepines and containing α ₄β ₃δ subunits. The results of ongoing clinical studies on the effect of the partial GABA _A agonist THIP on human sleep pattern show that the functional consequences of a directly acting agonist are distinctly different from those seen after administration of GABA _A receptor modulators, such as benzodiazepines. In the light of the interest in partial GABA _A receptor agonists as potential therapeutics, structure-activity studies of a number of analogues of 4-PIOL, a low-efficacy partial GABA _A agonist derived from THIP, have been performed. In this connection, a series of GABA _A ligands has been developed showing pharmacological profiles ranging from low-efficacy partial GABA _A agonist activity to selective antagonist effect.