Abstract

GABAC receptors are the least studied of the three major classes of GABA receptors. The physiological roles of GABAC receptors are still being unravelled and the pharmacology of these receptors is being developed. A range of agents has been described that act on GABAC receptors with varying degrees of specificity as agonists, partial agonists, antagonists and allosteric modulators. Pharmacological differences are known to exist between subtypes of cloned GABAC receptors that have been cloned from mammalian sources. There is evidence for functional GABAC receptors in the retina, spinal cord, superior colliculus, pituitary and gastrointestinal tract. Given the lower abundance and less widespread distribution of GABAC receptors in the CNS compared to GABAA receptors, GABAC receptors may be a more selective drug target than GABAA receptors. The major indications for drugs acting on GABAC receptors are in the treatment of visual, sleep and cognitive disorders. The most promising leads are THIP, a GABAC receptor antagonist in addition to its well known activity as a GABAA receptor partial agonist, which is being evaluated for sleep therapy, and CGP36742, an orally active GABAB and GABAC receptor antagonist, which enhances cognition. Analogues of THIP and CGP36742, such as aza-THIP, that are selective for GABAC receptors are being developed. TPMPA and related compounds such as P4MPA, PPA and SEPI are also important leads for the development of systemically active selective GABAC receptor antagonists.

Keywords: gabac receptors, gabac receptor antagonist, cgp36742, aza-thip