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.2015-09-092015-09-092010Journal of Medicinal Chemistry, 2010; 53(23):8354-83610022-26231520-4804http://hdl.handle.net/2440/94253We 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.enCopyright © 2010 American Chemical SocietyCell LineAnimalsXenopus laevisRatsSpodopteraIbotenic AcidReceptors, GlutamateExcitatory Amino Acid AntagonistsCrystallography, X-RayModels, MolecularJournal article003001563710.1021/jm101218a0002847384000142-s2.0-7864988092394240