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

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Structure and pharmacology of 4,5,6,7-tetrahydroisothiazolo [5,4-c]pyridin-3-ol (Thio-THIP), an agonist/antagonist at GABA(A) receptors. / Brehm, L.; Ebert, B.; Kristiansen, U.; Wafford, K. A.; Kemp, J. A.; Krogsgaard-Larsen, P.

In: European Journal of Medicinal Chemistry, Vol. 32, No. 4, 1997, p. 357-363.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Brehm, L, Ebert, B, Kristiansen, U, Wafford, KA, Kemp, JA & Krogsgaard-Larsen, P 1997, 'Structure and pharmacology of 4,5,6,7-tetrahydroisothiazolo [5,4-c]pyridin-3-ol (Thio-THIP), an agonist/antagonist at GABA(A) receptors', European Journal of Medicinal Chemistry, vol. 32, no. 4, pp. 357-363. https://doi.org/10.1016/S0223-5234(97)89089-7

APA

Brehm, L., Ebert, B., Kristiansen, U., Wafford, K. A., Kemp, J. A., & Krogsgaard-Larsen, P. (1997). Structure and pharmacology of 4,5,6,7-tetrahydroisothiazolo [5,4-c]pyridin-3-ol (Thio-THIP), an agonist/antagonist at GABA(A) receptors. European Journal of Medicinal Chemistry, 32(4), 357-363. https://doi.org/10.1016/S0223-5234(97)89089-7

Vancouver

Brehm L, Ebert B, Kristiansen U, Wafford KA, Kemp JA, Krogsgaard-Larsen P. Structure and pharmacology of 4,5,6,7-tetrahydroisothiazolo [5,4-c]pyridin-3-ol (Thio-THIP), an agonist/antagonist at GABA(A) receptors. European Journal of Medicinal Chemistry. 1997;32(4):357-363. https://doi.org/10.1016/S0223-5234(97)89089-7

Author

Brehm, L. ; Ebert, B. ; Kristiansen, U. ; Wafford, K. A. ; Kemp, J. A. ; Krogsgaard-Larsen, P. / Structure and pharmacology of 4,5,6,7-tetrahydroisothiazolo [5,4-c]pyridin-3-ol (Thio-THIP), an agonist/antagonist at GABA(A) receptors. In: European Journal of Medicinal Chemistry. 1997 ; Vol. 32, No. 4. pp. 357-363.

Bibtex

@article{9918a1a56f944d1bbf72752e05f1ce77,
title = "Structure and pharmacology of 4,5,6,7-tetrahydroisothiazolo [5,4-c]pyridin-3-ol (Thio-THIP), an agonist/antagonist at GABA(A) receptors",
abstract = "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.",
keywords = "Cellular electrophysiology, GABA(A) antagonists, GABA(A) partial agonists, GABA(A) receptors, Heterocyclic carboxyl bioisosteres, Molecular pharmacology, Receptor subunits, Recombinant receptors, Structure-activity studies, X-ray crystallography",
author = "L. Brehm and B. Ebert and U. Kristiansen and Wafford, {K. A.} and Kemp, {J. A.} and P. Krogsgaard-Larsen",
note = "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.",
year = "1997",
doi = "10.1016/S0223-5234(97)89089-7",
language = "English",
volume = "32",
pages = "357--363",
journal = "European Journal of Medicinal Chemistry",
issn = "0223-5234",
publisher = "Elsevier Masson",
number = "4",

}

RIS

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 -

ID: 276332746