title: The respective N-hydroxypyrazole analogues of the classical glutamate receptor ligands ibotenic acid and (RS)-2-amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid.
abstract: We have determined the pharmacological activity of N-hydroxypyrazole analogues (3a and 4a) of the classical glutamate receptor ligands ibotenic acid and (RS)-2-amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid (AMAA), as well as substituted derivatives of these two compounds. The pharmacological profile of 3a is closer to that of thioibotenic acid rather than ibotenic acid, while 4a is a selective N-methyl-D-aspartic acid (NMDA) receptor agonist. Ring substitution of 3a and 4a leads to NMDA receptor antagonists. Whereas efficacy of 3a derivatives at mglu2 receptor decreases from agonism via partial agonism to antagonism with increasing substituent size, substitution abolishes affinity for mglu1 and mglu4 receptors. Ligand- and receptor-based modelling approaches assist in explaining these pharmacological trends among the metabotropic receptors and suggest a mechanism of partial agonism at mglu2 receptor similar to that proposed for the GluR2 glutamate receptor.
authors.affiliation: Department of Medicinal Chemistry, Danish University of Pharmaceutical Sciences, 2 Universitetsparken, DK-2100 Copenhagen, Denmark. rac@dfuni.dk
authors.forename: Rasmus P
authors.initials: RP
authors.lastname: Clausen
authors.forename: Kasper B
authors.initials: KB
authors.lastname: Hansen
authors.forename: Patrizia
authors.initials: P
authors.lastname: Calí
authors.forename: Birgitte
authors.initials: B
authors.lastname: Nielsen
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Greenwood
authors.forename: Mikael
authors.initials: M
authors.lastname: Begtrup
authors.forename: Jan
authors.initials: J
authors.lastname: Egebjerg
authors.forename: Hans
authors.initials: H
authors.lastname: Bräuner-Osborne
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives* / Q000378:metabolism; D000409:Alanine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000378:metabolism / Q000494:pharmacology*; D018698:Glutamic Acid / Q000737:chemistry / Q000494:pharmacology; D007051:Ibotenic Acid / Q000378:metabolism / Q000494:pharmacology; D007608:Kainic Acid / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D008564:Membrane Potentials / Q000187:drug effects; D008958:Models, Molecular; D016202:N-Methylaspartate / Q000378:metabolism / Q000494:pharmacology; D011720:Pyrazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017470:Receptors, Glutamate / Q000737:chemistry / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013816:Thermodynamics; D014316:Tritium; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism / Q000494:pharmacology
chemical_list: D018690:Excitatory Amino Acid Agonists; D008024:Ligands; D011720:Pyrazoles; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D014316:Tritium; C069052:CGP 39653; C024314:N-acetylalanyl-N-methylamide; D007051:Ibotenic Acid; D018698:Glutamic Acid; C031280:pyrazole; D016202:N-Methylaspartate; D015763:2-Amino-5-phosphonovalerate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D000409:Alanine; D007608:Kainic Acid