Biostructural and Pharmacological Studies of Bicyclic Analogues of the 3-Isoxazolol Glutamate Receptor Agonist Ibotenic Acid

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• 作者：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 ; Rasmus P. Cl
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：December 9, 2010
• 年：2010
• 卷：53
• 期：23
• 页码：8354-8361
• 全文大小：934K
• 年卷期：v.53,no.23(December 9, 2010)
• ISSN：1520-4804

文摘

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.