STRUCTURE AND PHARMACOLOGY OF 4,5,6,7-TETRAHYDROISOTHIAZOLO[5,4-C]PYRIDIN-3-OL (THIO-THIP), AN AGONIST ANTAGONIST AT GABA(A) RECEPTORS/

4,5,6,7-Tetrahydroisothiazolo[5,4-c]pyridin-3-ol (Thio-THIP), an analo gue of the potent and efficacious partial GABA, agonist, 4,5,6,7-tetra hydroisoxazolo[5,4-c]pyridin-3-ol (THIP), shows rather potent agonist effects at spinal GABA(A) receptors in vivo, but remarkably low affini ty for brain GABA(A) receptors in vitro. thyl-4,5,6,7-tetrahydropyrazo lo[5,4-c]pyridin-3-ol (2-Me-Aza-THIP) does not bind detectably to GABA (A) receptors. The conformation of the molecule of Thio-THIP, which ha s now been determined by an X-ray crystallographic analysis, is very s imilar to those previously described for THIP and 2-Me-Aza-THIP. At hu man GABA(A) receptors of alpha(3) beta(2) gamma(2) or alpha(5) beta(3) gamma(2) subunit configurations, expressed in Xenopus oocytes, at whi ch THIP shows low- (44%) or high-efficacy (99%) GABA(A) agonism, respe ctively, Thio-THIP was shown to be a competitive antagonist. At GABA(A ) receptors in cultured cerebellar granule cells, Thio-THIP turned out to be a weak low-efficacy (2-9%) partial GABA(A) agonist.