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 Citations (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.

Original language	English
Journal	European Journal of Pharmacology
Volume	486
Issue number	3
Pages (from-to)	241-50
ISSN	0014-2999
DOIs	https://doi.org/10.1016/j.ejphar.2003.12.033
Publication status	Published - 23 Feb 2004

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

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10.1016/j.ejphar.2003.12.033

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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, vol. 486, no. 3, pp. 241-50. https://doi.org/10.1016/j.ejphar.2003.12.033

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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.",

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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

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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

Keywords

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