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 characteri zation. Whereas full agonists and antagonists at GABA(A) receptors, fo r different reasons, may be difficult to use therapeutically, partial GABA(A) agonists may have therapeutic interest. The efficacious partia l GABA(A) agonist, THIP, shows analgesic and anxiolytic effects in man , but THIP is ineffective as an antiepileptic agent, and PET studies h ave disclosed that THIP increases glucose metabolism in epileptic pati ents and human volunteers. In principle, GABA(A) antagonists may be us ed therapeutically in Alzheimer's disease and schizophrenia, but low-e fficacy 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 relati ve efficacies have been developed.