3pd8

Publication Abstract from PubMed

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.

Biostructural and Pharmacological Studies of Bicyclic Analogues of the 3-Isoxazolol Glutamate Receptor Agonist Ibotenic Acid.,Frydenvang K, Pickering DS, Greenwood JR, Krogsgaard-Larsen N, Brehm L, Nielsen B, Vogensen SB, Hald H, Kastrup JS, Krogsgaard-Larsen P, Clausen RP J Med Chem. 2010 Nov 10. PMID:21067182^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.