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

Research output: Contribution to journalJournal articleResearchpeer-review

Karla Andrea Frydenvang, Darryl S Pickering, Jeremy R Greenwood, Niels Krogsgaard-Larsen, Lotte Brehm, Birgitte Nielsen, Stine Byskov Vogensen, Helle Hald, Jette Sandholm Kastrup, Povl Krogsgaard-Larsen, Rasmus Prætorius Clausen

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.
Original languageEnglish
JournalJournal of Medicinal Chemistry
Volume53
Issue number23
Pages (from-to)8354-8361
ISSN0022-2623
DOIs
Publication statusPublished - 10 Nov 2010

ID: 32258776