GABA(A) and GABA(B) receptor agonists, partial agonists, antagonists and modulators: Design and therapeutic prospects

A large number of highly selective GABA(A) and, more recently, GABA(B) receptor ligands have been developed and used for receptor characterization. Whereas full agonists and antagonists at GABA(A) receptors, for different reasons, may be difficult to use therapeutically, partial GABA(A) agonists may have therapeutic interest. The efficacious partial GABA(A) agonist, THIP, shows analgesic and anxiolytic effects in man, but THIP is ineffective as an antiepileptic agent, and PET studies have disclosed that THIP increases glucose metabolism in epileptic patients and human volunteers. In principle, GABA(A) antagonists may be used therapeutically in Alzheimer's disease and schizophrenia, but low-efficacy partial GABA(A) agonists may have particular interest in these disorders. Using the nonannulated THIP analogue, 4-PIOL, as a lead, a series of partial GABA(A) agonists showing a broad spectrum of relative efficacies have been developed.