AbstractThe GABAA receptor system is implicated in a number of neurological and psychiatric diseases, making GABAA 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 GABAA receptor complex, reflecting the very strict structural requirements for GABAA receptor recognition and activation. Within the series of compounds showing agonist activity at the GABAA receptor site that have been developed, most of the ligands are structurally derived from the GABAA agonists muscimol, THIP, or isoguvacine, which we developed in the initial stages of the project. Using recombinant GABAA 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 GABAA receptor agonists as potential therapeutics, structure–activity studies of a number of analogs of 4‐PIOL, a low‐efficacy partial GABAA agonist derived from THIP, have been performed. In this connection, a series of GABAA ligands has been developed that exhibit pharmacological profiles from moderately potent low‐efficacy partial GABAA agonist activity to potent and selective antagonist effects. Very little information is available on direct‐acting GABAA receptor agonists in clinical studies. However, the results of clinical studies on the effect of the partial GABAA 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 GABAA receptor modulators, such as benzodiazepines and barbiturates. © 2002 The Japan Chemical Journal Forum and Wiley Periodicals, Inc., Chem Rec 2: 419–430; 2002: Published online in Wiley Interscience (www.interscience.wiley.com) DOI 10.1002/tcr.10040