Ibotenic acid and thioibotenic acid: a remarkable difference in activity at group III metabotropic glutamate receptors.
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.
Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, 2 Universitetsparken, Copenhagen, DK-2100, Denmark.
Mette B
MB
Hermit
Jeremy R
JR
Greenwood
Birgitte
B
Nielsen
Lennart
L
Bunch
Charlotte G
CG
Jørgensen
Henrik T
HT
Vestergaard
Tine B
TB
Stensbøl
Connie
C
Sanchez
Povl
P
Krogsgaard-Larsen
Ulf
U
Madsen
Hans
H
Bräuner-Osborne
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018690:Excitatory Amino Acid Agonists / Q000737:chemistry / Q000494:pharmacology*; D007051:Ibotenic Acid / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D011869:Radioligand Assay; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000145:classification / Q000502:physiology; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*
D018690:Excitatory Amino Acid Agonists; D008024:Ligands; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles; C494664:thioibotenic acid; D007051:Ibotenic Acid