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https://hdl.handle.net/2440/94253
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dc.contributor.author | Frydenvang, K. | - |
dc.contributor.author | Pickering, D.S. | - |
dc.contributor.author | Greenwood, J.R. | - |
dc.contributor.author | Krogsgaard-Larsen, N. | - |
dc.contributor.author | Brehm, L. | - |
dc.contributor.author | Nielsen, B. | - |
dc.contributor.author | Vogensen, S.B. | - |
dc.contributor.author | Hald, H. | - |
dc.contributor.author | Kastrup, J.S. | - |
dc.contributor.author | Krogsgaard-Larsen, P. | - |
dc.contributor.author | Clausen, R.P. | - |
dc.date.issued | 2010 | - |
dc.identifier.citation | Journal of Medicinal Chemistry, 2010; 53(23):8354-8361 | - |
dc.identifier.issn | 0022-2623 | - |
dc.identifier.issn | 1520-4804 | - |
dc.identifier.uri | http://hdl.handle.net/2440/94253 | - |
dc.description.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. | - |
dc.description.statementofresponsibility | 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 | - |
dc.language.iso | en | - |
dc.publisher | American Chemical Society | - |
dc.rights | Copyright © 2010 American Chemical Society | - |
dc.source.uri | http://dx.doi.org/10.1021/jm101218a | - |
dc.subject | Cell Line | - |
dc.subject | Animals | - |
dc.subject | Xenopus laevis | - |
dc.subject | Rats | - |
dc.subject | Spodoptera | - |
dc.subject | Ibotenic Acid | - |
dc.subject | Receptors, Glutamate | - |
dc.subject | Excitatory Amino Acid Antagonists | - |
dc.subject | Crystallography, X-Ray | - |
dc.subject | Models, Molecular | - |
dc.title | Biostructural and pharmacological studies of bicyclic analogues of the 3-isoxazolol glutamate receptor agonist ibotenic acid | - |
dc.type | Journal article | - |
dc.identifier.doi | 10.1021/jm101218a | - |
pubs.publication-status | Published | - |
Appears in Collections: | Aurora harvest 2 Chemistry and Physics publications |
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