Structure and pharmacology of 4,5,6,7-tetrahydroisothiazolo[5,4-c]pyridin-3-ol (Thio-THIP), an agonist/antagonist at GABAA receptors

Summary 4,5,6,7-Tetrahydroisothiazolo[5,4- c ]pyridin-3-ol (Thio-THIP), an analogue of the potent and efficacious partial GABA A agonist, 4,5,6,7-tetrahydroisoxazolo[5,4- c ]pyridin-3-ol (THIP), shows rather potent agonist effects at spinal GABA A receptors in vivo, but remarkably low affinity for brain GABA A receptors in vitro. 2-Methyl-4,5,6,7-tetrahydropyrazolo[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 has now been determined by an X-ray crystallographic analysis, is very similar to those previously described for THIP and 2-Me-Aza-THIP. At human GABA A receptors of α 3 β 2 γ 2 or α 5 β 3 γ 2 subunit configurations, expressed in Xenopus oocytes, at which THIP shows low- (44%) or high-efficacy (99%) GABA A agonism, respectively, 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.