Ibotenic acid and thioibotenic acid: a remarkable difference in activity at group III metabotropic glutamate receptors
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Ibotenic acid and thioibotenic acid : a remarkable difference in activity at group III metabotropic glutamate receptors. / Hermit, Mette B; Greenwood, Jeremy R; Nielsen, Birgitte; Bunch, Lennart; Jørgensen, Charlotte G; Vestergaard, Henrik T; Stensbøl, Tine B; Sanchez, Connie; Krogsgaard-Larsen, Povl; Madsen, Ulf; Bräuner-Osborne, Hans.
In: European Journal of Pharmacology, Vol. 486, No. 3, 23.02.2004, p. 241-50.Research output: Contribution to journal › Journal article › Research › peer-review
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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
VL - 486
SP - 241
EP - 250
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
IS - 3
ER -
ID: 45596371