☆ 4.7 Article

Biostructural and Pharmacological Studies of Bicyclic Analogues of the 3-Isoxazolol Glutamate Receptor Agonist Ibotenic Acid

JOURNAL OF MEDICINAL CHEMISTRY (2010)

期刊

JOURNAL OF MEDICINAL CHEMISTRY

卷 53, 期 23, 页码 8354-8361

出版社

AMER CHEMICAL SOC

DOI: 10.1021/jm101218a

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Chemistry, Medicinal

资金

Lundbeck Foundation
Danish Medical Research Council
DANSYNC (Danish Centre for Synchrotron Based Research)
European Community

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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 (5)-5 in the GluA2 agonist binding domain. WaterMap analysis of the GluA2 and. GluA4 binding pockets with (R)-4 and (5)-5 suggests that the energy of hydration sites is ligand dependent, which may explain the observed selectivity.

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