Structure鈥揂ctivity Relationship Study of Ionotropic Glutamate Receptor Antagonist (2S,3R)-3-(3-Carboxyphenyl)pyrrolidine-2-carboxylic Acid

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• 作者：Niels Krogsgaard-Larsen ; Morten Storgaard ; Charlotte M酶ller ; Charles S. Demmer ; Jeanette Hansen ; Liwei Han ; Rune N. Monrad ; Birgitte Nielsen ; Daniel Tapken ; Darryl S. Pickering ; Jette S. Kastrup ; Karla Frydenvang ; Lennart Bunch
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：August 13, 2015
• 年：2015
• 卷：58
• 期：15
• 页码：6131-6150
• 全文大小：820K
• ISSN：1520-4804

文摘

Herein we describe the first structure鈥揳ctivity relationship study of the broad-range iGluR antagonist (2S,3R)-3-(3-carboxyphenyl)pyrrolidine-2-carboxylic acid (1) by exploring the pharmacological effect of substituents in the 4, 4鈥? or 5鈥?positions and the bioisosteric substitution of the distal carboxylic acid for a phosphonic acid moiety. Of particular interest is a hydroxyl group in the 4鈥?position 2a which induced a preference in binding affinity for homomeric GluK3 over GluK1 (K_i = 0.87 and 4.8 渭M, respectively). Two X-ray structures of ligand binding domains were obtained: 2e in GluA2-LBD and 2f in GluK1-LBD, both at 1.9 脜 resolution. Compound 2e induces a D1鈥揇2 domain opening in GluA2-LBD of 17.3鈥?8.8掳 and 2f a domain opening in GluK1-LBD of 17.0鈥?7.5掳 relative to the structures with glutamate. The pyrrolidine-2-carboxylate moiety of 2e and 2f shows a similar binding mode as kainate. The 3-carboxyphenyl ring of 2e and 2f forms contacts comparable to those of the distal carboxylate in kainate.