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-tetrahydroisoxazoIo [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 α₃β₂γ₂ or α₅β₃γ₂ 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.