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

• Published in: European journal of pharmacology Vol. 486; no. 3; pp. 241 - 250
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 23.02.2004; Elsevier
• Subjects: Animals; Biological and medical sciences; CHO Cells; Conformational energy; Cricetinae; Cricetulus; Docking; Excitatory Amino Acid Agonists - chemistry; Excitatory Amino Acid Agonists - pharmacology; Glutamate receptor; Group III agonist; Homology model; Ibotenic acid; Ibotenic Acid - chemistry; Ibotenic Acid - pharmacology; In Vitro Techniques; Ligands; Male; Medical sciences; mGlu receptor; Mice; Models, Molecular; Molecular Conformation; Pharmacology. Drug treatments; Radioligand Assay; Rats; Receptors, Metabotropic Glutamate - agonists; Receptors, Metabotropic Glutamate - classification; Receptors, Metabotropic Glutamate - physiology; Thiazoles - chemistry; Thiazoles - pharmacology; Thioibotenic acid; Ibotenic acid; Group III agonist; Thioibotenic acid; Conformational energy; Homology model; Docking; Glutamate receptor; mGlu receptor; Agonist; Homology; Group III mglu glutamate receptor; Models; Biological receptor
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2003.12.033

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 μm) 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 mGlu 1 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.