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

TY - JOUR

T1 - 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

AU - Clausen, Rasmus P

AU - Hansen, Kasper B

AU - Calí, Patrizia

AU - Nielsen, Birgitte

AU - Greenwood, Jeremy R

AU - Begtrup, Mikael

AU - Egebjerg, Jan

AU - Bräuner-Osborne, Hans

PY - 2004/9/19

Y1 - 2004/9/19

N2 - 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.

AB - 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.

KW - 2-Amino-5-phosphonovalerate

KW - Alanine

KW - Animals

KW - Binding Sites

KW - Binding, Competitive

KW - Brain

KW - CHO Cells

KW - Cell Membrane

KW - Cricetinae

KW - Cricetulus

KW - Dose-Response Relationship, Drug

KW - Excitatory Amino Acid Agonists

KW - Glutamic Acid

KW - Ibotenic Acid

KW - Kainic Acid

KW - Ligands

KW - Membrane Potentials

KW - Models, Molecular

KW - N-Methylaspartate

KW - Pyrazoles

KW - Rats

KW - Receptors, Glutamate

KW - Receptors, N-Methyl-D-Aspartate

KW - Thermodynamics

KW - Tritium

KW - alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid

U2 - 10.1016/j.ejphar.2004.07.049

DO - 10.1016/j.ejphar.2004.07.049

M3 - Journal article

C2 - 15363949

SN - 0014-2999

VL - 499

SP - 35

EP - 44

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

IS - 1-2

ER -