Design and Synthesis of a Series of l-trans-4-Substituted Prolines as Selective Antagonists for the Ionotropic Glutamate Receptors Including Functional and X-ray Crystallographic Studies of New Subtype Selective Kainic Acid Receptor Subtype 1 (GluK1) Antagonist (2S,4R)-4-(2-Carboxyphenoxy)pyrrolidin

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• 作者：Niels Krogsgaard-Larsen ; Claudia G. Delgar ; Karina Koch ; Patricia M. G. E. Brown ; Charlotte Møller ; Liwei Han ; Tri H. V. Huynh ; Stinne W. Hansen ; Birgitte Nielsen ; Derek Bowie ; Darryl S. Pickering ; Jette Sandholm Kastrup ; Karla Frydenvang ; Lennart Bunch
• 刊名：Journal of Medicinal Chemistry
• 出版年：2017
• 出版时间：January 12, 2017
• 年：2017
• 卷：60
• 期：1
• 页码：441-457
• 全文大小：680K
• ISSN：1520-4804

文摘

Ionotropic glutamate receptor antagonists are valuable tool compounds for studies of neurological pathways in the central nervous system. On the basis of rational ligand design, a new class of selective antagonists, represented by (2S,4R)-4-(2-carboxyphenoxy)pyrrolidine-2-carboxylic acid (1b), for cloned homomeric kainic acid receptors subtype 1 (GluK1) was attained (K_i = 4 μM). In a functional assay, 1b displayed full antagonist activity with IC₅₀ = 6 ± 2 μM. A crystal structure was obtained of 1b when bound in the ligand binding domain of GluK1. A domain opening of 13–14° was seen compared to the structure with glutamate, consistent with 1b being an antagonist. A structure–activity relationship study showed that the chemical nature of the tethering atom (C, O, or S) linking the pyrrolidine ring and the phenyl ring plays a key role in the receptor selectivity profile and that substituents on the phenyl ring are well accommodated by the GluK1 receptor.