TY - JOUR
T1 - Structure and pharmacology of 4,5,6,7-tetrahydroisothiazolo [5,4-c]pyridin-3-ol (Thio-THIP), an agonist/antagonist at GABA(A) receptors
AU - Brehm, L.
AU - Ebert, B.
AU - Kristiansen, U.
AU - Wafford, K. A.
AU - Kemp, J. A.
AU - Krogsgaard-Larsen, P.
N1 - Funding Information:
This work was supported by grants from the Lundbeck Foundation, the Alfred Benzon Foundation and the Danish State Biotechnology Programme (1991-1995). The assistance of F Hansen with the X-ray data collection and the secretarial assistance of A Nordly and AM Nielsen is gratefully acknowledged. The cultured cerebellar granule cells were kindly provided by A Schousboe, The Royal Danish School of Pharmacy, Copenhagen.
PY - 1997
Y1 - 1997
N2 - 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.
AB - 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.
KW - Cellular electrophysiology
KW - GABA(A) antagonists
KW - GABA(A) partial agonists
KW - GABA(A) receptors
KW - Heterocyclic carboxyl bioisosteres
KW - Molecular pharmacology
KW - Receptor subunits
KW - Recombinant receptors
KW - Structure-activity studies
KW - X-ray crystallography
UR - http://www.scopus.com/inward/record.url?scp=0030915294&partnerID=8YFLogxK
U2 - 10.1016/S0223-5234(97)89089-7
DO - 10.1016/S0223-5234(97)89089-7
M3 - Journal article
AN - SCOPUS:0030915294
VL - 32
SP - 357
EP - 363
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
IS - 4
ER -