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Type: Journal article
Title: Biostructural and pharmacological studies of bicyclic analogues of the 3-isoxazolol glutamate receptor agonist ibotenic acid
Author: Frydenvang, K.
Pickering, D.S.
Greenwood, J.R.
Krogsgaard-Larsen, N.
Brehm, L.
Nielsen, B.
Vogensen, S.B.
Hald, H.
Kastrup, J.S.
Krogsgaard-Larsen, P.
Clausen, R.P.
Citation: Journal of Medicinal Chemistry, 2010; 53(23):8354-8361
Publisher: American Chemical Society
Issue Date: 2010
ISSN: 0022-2623
Statement of
Karla Frydenvang, Darryl S. Pickering, Jeremy R. Greenwood, Niels Krogsgaard-Larsen, Lotte Brehm, Birgitte Nielsen, Stine B. Vogensen, Helle Hald, Jette S. Kastrup, Povl Krogsgaard-Larsen, and Rasmus P. Clausen
Abstract: We describe an improved synthesis and detailed pharmacological characterization of the conformationally restricted analogue of the naturally occurring nonselective glutamate receptor agonist ibotenic acid (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-7-carboxylic acid (7-HPCA, 5) at AMPA receptor subtypes. Compound 5 was shown to be a subtype-discriminating agonist at AMPA receptors with higher binding affinity and functional potency at GluA1/2 compared to GluA3/4, unlike the isomeric analogue (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-5-carboxylic acid (5-HPCA, 4) that binds to all AMPA receptor subtypes with comparable potency. Biostructural X-ray crystallographic studies of 4 and 5 reveal different binding modes of (R)-4 and (S)-5 in the GluA2 agonist binding domain. WaterMap analysis of the GluA2 and GluA4 binding pockets with (R)-4 and (S)-5 suggests that the energy of hydration sites is ligand dependent, which may explain the observed selectivity.
Keywords: Cell Line
Xenopus laevis
Ibotenic Acid
Receptors, Glutamate
Excitatory Amino Acid Antagonists
Crystallography, X-Ray
Models, Molecular
Rights: Copyright © 2010 American Chemical Society
DOI: 10.1021/jm101218a
Appears in Collections:Aurora harvest 2
Chemistry and Physics publications

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