Specific GABA A agonists and partial agonists

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. © 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