The GABA_A receptor system is implicated in a number of neurological and psychiatric diseases, 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. Within the series of compounds showing agonist activity at the GABA_A receptor site that have been developed, most of the ligands are structurally derived from the GABA_A agonists muscimol, THIP, or isoguvacine, which we developed in the initial stages of the project. Using recombinant GABA_A receptors, functional selectivity was demonstrated for a number of compounds, including THIP, showing highly subunit-dependent potency and maximal response. In light of the interest in partial GABA _A receptor agonists as potential therapeutics, structure-activity studies of a number of analogs 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 that exhibit pharmacological profiles from moderately potent low-efficacy partial GABA _A agonist activity to potent and selective antagonist effects. Very little information is available on direct-acting GABA_A receptor agonists in clinical studies. However, the results of clinical studies on the effect of the partial GABA_A agonist THIP on human sleep patterns show that the functional consequences of a direct-acting agonist are different from those seen after the administration of GABA_A receptor modulators, such as benzodiazepines and barbiturates.