GABA A agonists and partial agonists: THIP (Gaboxadol) as a non-opioid analgesic and a novel type of hypnotic

Abstract

The GABA A receptor system is implicated in a number of central nervous system (CNS) disorders, 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. A large number of the compounds showing agonist activity at the GABA A receptor site are structurally derived from the GABA A agonists muscimol, THIP (Gaboxadol), or isoguvacine, which we developed at the initial stage of the project. Using recombinant GABA A receptors, functional selectivity has been shown for a number of compounds, including THIP, showing subunit-dependent potency and maximal response. The pharmacological and clinical activities of THIP probably reflect its potent effects at extrasynaptic GABA A receptors insensitive to benzodiazepines and containing α 4β 3δ subunits. The results of ongoing clinical studies on the effect of the partial GABA A agonist THIP on human sleep pattern show that the functional consequences of a directly acting agonist are distinctly different from those seen after administration of GABA A receptor modulators, such as benzodiazepines. In the light of the interest in partial GABA A receptor agonists as potential therapeutics, structure-activity studies of a number of analogues 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 showing pharmacological profiles ranging from low-efficacy partial GABA A agonist activity to selective antagonist effect.