Discovery of GluN2A-Selective NMDA Receptor Positive Allosteric Modulators (PAMs): Tuning Deactivation Kinetics via Structure-Based Design

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• 作者：Matthew Volgraf ; Benjamin D. Sellers ; Yu Jiang ; Guosheng Wu ; Cuong Q. Ly ; Elisia Villemure ; Richard M. Pastor ; Po-wai Yuen ; Aijun Lu ; Xifeng Luo ; Mingcui Liu ; Shun Zhang ; Liang Sun ; Yuhong Fu ; Patrick J. Lupardus ; Heidi J.A. Wallweber ; Bianca M. Liederer ; Gauri Deshmukh ; Emile Plise ; Suzanne Tay ; Paul Reynen ; James Herrington ; Amy Gustafson ; Yichin Liu ; Akim Dirksen ; Matthias G. A. Dietz ; Yanzhou Liu ; Tzu-Ming Wang ; Jesse E. Hanson ; David Hackos ; Kimberly Scearce-Levie ; Jacob B. Schwarz
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：March 24, 2016
• 年：2016
• 卷：59
• 期：6
• 页码：2760-2779
• 全文大小：873K
• ISSN：1520-4804

文摘

The N-methyl-d-aspartate receptor (NMDAR) is a Na⁺ and Ca²⁺ permeable ionotropic glutamate receptor that is activated by the coagonists glycine and glutamate. NMDARs are critical to synaptic signaling and plasticity, and their dysfunction has been implicated in a number of neurological disorders, including schizophrenia, depression, and Alzheimer’s disease. Herein we describe the discovery of potent GluN2A-selective NMDAR positive allosteric modulators (PAMs) starting from a high-throughput screening hit. Using structure-based design, we sought to increase potency at the GluN2A subtype, while improving selectivity against related α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). The structure–activity relationship of channel deactivation kinetics was studied using a combination of electrophysiology and protein crystallography. Effective incorporation of these strategies resulted in the discovery of GNE-0723 (46), a highly potent and brain penetrant GluN2A-selective NMDAR PAM suitable for in vivo characterization.