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

Rasmus P Clausen; Kasper B Hansen; Patrizia Calí; Birgitte Nielsen; Jeremy R Greenwood; Mikael Begtrup; Jan Egebjerg; Hans Bräuner-Osborne

doi:10.1016/j.ejphar.2004.07.049

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

Rasmus P Clausen, Kasper B Hansen, Patrizia Calí, Birgitte Nielsen, Jeremy R Greenwood, Mikael Begtrup, Jan Egebjerg, Hans Bräuner-Osborne

21 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	European Journal of Pharmacology
Vol/bind	499
Udgave nummer	1-2
Sider (fra-til)	35-44
Antal sider	10
ISSN	0014-2999
DOI	https://doi.org/10.1016/j.ejphar.2004.07.049
Status	Udgivet - 19 sep. 2004

Adgang til dokumentet

10.1016/j.ejphar.2004.07.049

Citationsformater

Clausen, R. P., Hansen, K. B., Calí, P., Nielsen, B., Greenwood, J. R., Begtrup, M., Egebjerg, J., & Bräuner-Osborne, H. (2004). 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. European Journal of Pharmacology, 499(1-2), 35-44. https://doi.org/10.1016/j.ejphar.2004.07.049

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. / Clausen, Rasmus P; Hansen, Kasper B; Calí, Patrizia et al.

I: European Journal of Pharmacology, Bind 499, Nr. 1-2, 19.09.2004, s. 35-44.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Clausen, RP, Hansen, KB, Calí, P, Nielsen, B, Greenwood, JR, Begtrup, M, Egebjerg, J & Bräuner-Osborne, H 2004, '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', European Journal of Pharmacology, bind 499, nr. 1-2, s. 35-44. https://doi.org/10.1016/j.ejphar.2004.07.049

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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.",

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author = "Clausen, {Rasmus P} and Hansen, {Kasper B} and Patrizia Cal{\'i} and Birgitte Nielsen and Greenwood, {Jeremy R} and Mikael Begtrup and Jan Egebjerg and Hans Br{\"a}uner-Osborne",

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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

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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.

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KW - Binding, Competitive

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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

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KW - Membrane Potentials

KW - Models, Molecular

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KW - Receptors, N-Methyl-D-Aspartate

KW - Thermodynamics

KW - Tritium

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

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JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

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ER -

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

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