Biostructural and pharmacological studies of bicyclic analogues of the 3-isoxazolol glutamate receptor agonist ibotenic acid

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dc.contributor.authorFrydenvang, K.
dc.contributor.authorPickering, D.S.
dc.contributor.authorGreenwood, J.R.
dc.contributor.authorKrogsgaard-Larsen, N.
dc.contributor.authorBrehm, L.
dc.contributor.authorNielsen, B.
dc.contributor.authorVogensen, S.B.
dc.contributor.authorHald, H.
dc.contributor.authorKastrup, J.S.
dc.contributor.authorKrogsgaard-Larsen, P.
dc.contributor.authorClausen, R.P.
dc.date.issued2010
dc.description.abstractWe 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.
dc.description.statementofresponsibilityKarla 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
dc.identifier.citationJournal of Medicinal Chemistry, 2010; 53(23):8354-8361
dc.identifier.doi10.1021/jm101218a
dc.identifier.issn0022-2623
dc.identifier.issn1520-4804
dc.identifier.urihttp://hdl.handle.net/2440/94253
dc.language.isoen
dc.publisherAmerican Chemical Society
dc.rightsCopyright © 2010 American Chemical Society
dc.source.urihttps://doi.org/10.1021/jm101218a
dc.subjectCell Line
dc.subjectAnimals
dc.subjectXenopus laevis
dc.subjectRats
dc.subjectSpodoptera
dc.subjectIbotenic Acid
dc.subjectReceptors, Glutamate
dc.subjectExcitatory Amino Acid Antagonists
dc.subjectCrystallography, X-Ray
dc.subjectModels, Molecular
dc.titleBiostructural and pharmacological studies of bicyclic analogues of the 3-isoxazolol glutamate receptor agonist ibotenic acid
dc.typeJournal article
pubs.publication-statusPublished

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