Ibotenic acid and thioibotenic acid: a remarkable difference in activity at group III metabotropic glutamate receptors

Mette B Hermit; Jeremy R Greenwood; Birgitte Nielsen; Lennart Bunch; Charlotte G Jørgensen; Henrik T Vestergaard; Tine B Stensbøl; Connie Sanchez; Povl Krogsgaard-Larsen; Ulf Madsen; Hans Bräuner-Osborne

doi:10.1016/j.ejphar.2003.12.033

Ibotenic acid and thioibotenic acid: a remarkable difference in activity at group III metabotropic glutamate receptors

Mette B Hermit, Jeremy R Greenwood, Birgitte Nielsen, Lennart Bunch, Charlotte G Jørgensen, Henrik T Vestergaard, Tine B Stensbøl, Connie Sanchez, Povl Krogsgaard-Larsen, Ulf Madsen, Hans Bräuner-Osborne

45 Citationer (Scopus)

Abstract

In this study, we have determined and compared the pharmacological profiles of ibotenic acid and its isothiazole analogue thioibotenic acid at native rat ionotropic glutamate (iGlu) receptors and at recombinant rat metabotropic glutamate (mGlu) receptors expressed in mammalian cell lines. Thioibotenic acid has a distinct pharmacological profile at group III mGlu receptors compared with the closely structurally related ibotenic acid; the former is a potent (low microm) agonist, whereas the latter is inactive. By comparing the conformational energy profiles of ibotenic and thioibotenic acid with the conformations preferred by the ligands upon docking to mGlu1 and models of the other mGlu subtypes, we propose that unlike other subtypes, group III mGlu receptor binding sites require a ligand conformation at an energy level which is prohibitively expensive for ibotenic acid, but not for thioibotenic acid. These studies demonstrate how subtle differences in chemical structures can result in profound differences in pharmacological activity.

Originalsprog	Engelsk
Tidsskrift	European Journal of Pharmacology
Vol/bind	486
Udgave nummer	3
Sider (fra-til)	241-50
ISSN	0014-2999
DOI	https://doi.org/10.1016/j.ejphar.2003.12.033
Status	Udgivet - 23 feb. 2004

Adgang til dokumentet

10.1016/j.ejphar.2003.12.033

Citationsformater

Hermit, M. B., Greenwood, J. R., Nielsen, B., Bunch, L., Jørgensen, C. G., Vestergaard, H. T., Stensbøl, T. B., Sanchez, C., Krogsgaard-Larsen, P., Madsen, U., & Bräuner-Osborne, H. (2004). Ibotenic acid and thioibotenic acid: a remarkable difference in activity at group III metabotropic glutamate receptors. European Journal of Pharmacology, 486(3), 241-50. https://doi.org/10.1016/j.ejphar.2003.12.033

Hermit, MB, Greenwood, JR, Nielsen, B , Bunch, L, Jørgensen, CG, Vestergaard, HT, Stensbøl, TB, Sanchez, C, Krogsgaard-Larsen, P , Madsen, U & Bräuner-Osborne, H 2004, 'Ibotenic acid and thioibotenic acid: a remarkable difference in activity at group III metabotropic glutamate receptors', European Journal of Pharmacology, bind 486, nr. 3, s. 241-50. https://doi.org/10.1016/j.ejphar.2003.12.033

@article{f1e3d47023244d71985e67bd0c19ff77,

title = "Ibotenic acid and thioibotenic acid: a remarkable difference in activity at group III metabotropic glutamate receptors",

abstract = "In this study, we have determined and compared the pharmacological profiles of ibotenic acid and its isothiazole analogue thioibotenic acid at native rat ionotropic glutamate (iGlu) receptors and at recombinant rat metabotropic glutamate (mGlu) receptors expressed in mammalian cell lines. Thioibotenic acid has a distinct pharmacological profile at group III mGlu receptors compared with the closely structurally related ibotenic acid; the former is a potent (low microm) agonist, whereas the latter is inactive. By comparing the conformational energy profiles of ibotenic and thioibotenic acid with the conformations preferred by the ligands upon docking to mGlu1 and models of the other mGlu subtypes, we propose that unlike other subtypes, group III mGlu receptor binding sites require a ligand conformation at an energy level which is prohibitively expensive for ibotenic acid, but not for thioibotenic acid. These studies demonstrate how subtle differences in chemical structures can result in profound differences in pharmacological activity.",

keywords = "Animals, CHO Cells, Cricetinae, Cricetulus, Excitatory Amino Acid Agonists, Ibotenic Acid, Ligands, Male, Mice, Models, Molecular, Molecular Conformation, Radioligand Assay, Rats, Receptors, Metabotropic Glutamate, Thiazoles",

author = "Hermit, {Mette B} and Greenwood, {Jeremy R} and Birgitte Nielsen and Lennart Bunch and J{\o}rgensen, {Charlotte G} and Vestergaard, {Henrik T} and Stensb{\o}l, {Tine B} and Connie Sanchez and Povl Krogsgaard-Larsen and Ulf Madsen and Hans Br{\"a}uner-Osborne",

year = "2004",

month = feb,

day = "23",

doi = "10.1016/j.ejphar.2003.12.033",

language = "English",

volume = "486",

pages = "241--50",

journal = "European Journal of Pharmacology",

issn = "0014-2999",

publisher = "Elsevier",

number = "3",

}

TY - JOUR

T1 - Ibotenic acid and thioibotenic acid

T2 - a remarkable difference in activity at group III metabotropic glutamate receptors

AU - Hermit, Mette B

AU - Greenwood, Jeremy R

AU - Nielsen, Birgitte

AU - Bunch, Lennart

AU - Jørgensen, Charlotte G

AU - Vestergaard, Henrik T

AU - Stensbøl, Tine B

AU - Sanchez, Connie

AU - Krogsgaard-Larsen, Povl

AU - Madsen, Ulf

AU - Bräuner-Osborne, Hans

PY - 2004/2/23

Y1 - 2004/2/23

N2 - In this study, we have determined and compared the pharmacological profiles of ibotenic acid and its isothiazole analogue thioibotenic acid at native rat ionotropic glutamate (iGlu) receptors and at recombinant rat metabotropic glutamate (mGlu) receptors expressed in mammalian cell lines. Thioibotenic acid has a distinct pharmacological profile at group III mGlu receptors compared with the closely structurally related ibotenic acid; the former is a potent (low microm) agonist, whereas the latter is inactive. By comparing the conformational energy profiles of ibotenic and thioibotenic acid with the conformations preferred by the ligands upon docking to mGlu1 and models of the other mGlu subtypes, we propose that unlike other subtypes, group III mGlu receptor binding sites require a ligand conformation at an energy level which is prohibitively expensive for ibotenic acid, but not for thioibotenic acid. These studies demonstrate how subtle differences in chemical structures can result in profound differences in pharmacological activity.

AB - In this study, we have determined and compared the pharmacological profiles of ibotenic acid and its isothiazole analogue thioibotenic acid at native rat ionotropic glutamate (iGlu) receptors and at recombinant rat metabotropic glutamate (mGlu) receptors expressed in mammalian cell lines. Thioibotenic acid has a distinct pharmacological profile at group III mGlu receptors compared with the closely structurally related ibotenic acid; the former is a potent (low microm) agonist, whereas the latter is inactive. By comparing the conformational energy profiles of ibotenic and thioibotenic acid with the conformations preferred by the ligands upon docking to mGlu1 and models of the other mGlu subtypes, we propose that unlike other subtypes, group III mGlu receptor binding sites require a ligand conformation at an energy level which is prohibitively expensive for ibotenic acid, but not for thioibotenic acid. These studies demonstrate how subtle differences in chemical structures can result in profound differences in pharmacological activity.

KW - Animals

KW - CHO Cells

KW - Cricetinae

KW - Cricetulus

KW - Excitatory Amino Acid Agonists

KW - Ibotenic Acid

KW - Ligands

KW - Male

KW - Mice

KW - Models, Molecular

KW - Molecular Conformation

KW - Radioligand Assay

KW - Rats

KW - Receptors, Metabotropic Glutamate

KW - Thiazoles

U2 - 10.1016/j.ejphar.2003.12.033

DO - 10.1016/j.ejphar.2003.12.033

M3 - Journal article

C2 - 14985045

SN - 0014-2999

VL - 486

SP - 241

EP - 250

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

IS - 3

ER -

Ibotenic acid and thioibotenic acid: a remarkable difference in activity at group III metabotropic glutamate receptors

Abstract

Adgang til dokumentet

Fingeraftryk

Citationsformater