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https://hdl.handle.net/2440/94253
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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 1520-4804 |
Statement of Responsibility: | 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 Animals Xenopus laevis Rats Spodoptera Ibotenic Acid Receptors, Glutamate Excitatory Amino Acid Antagonists Crystallography, X-Ray Models, Molecular |
Rights: | Copyright © 2010 American Chemical Society |
DOI: | 10.1021/jm101218a |
Published version: | http://dx.doi.org/10.1021/jm101218a |
Appears in Collections: | Aurora harvest 2 Chemistry and Physics publications |
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