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|Title:||Biostructural and pharmacological studies of bicyclic analogues of the 3-isoxazolol glutamate receptor agonist ibotenic acid|
|Citation:||Journal of Medicinal Chemistry, 2010; 53(23):8354-8361|
|Publisher:||American Chemical Society|
|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.|
Excitatory Amino Acid Antagonists
|Rights:||Copyright © 2010 American Chemical Society|
|Appears in Collections:||Aurora harvest 2|
Chemistry and Physics publications
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