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