학술논문
Discovery of GluN2A-Selective NMDA Receptor Positive Allosteric Modulators (PAMs): Tuning Deactivation Kinetics via Structure-Based Design.
Document Type
Article
Author
Volgraf, Matthew; Sellers, Benjamin D.; Yu Jiang; Guosheng Wu; Cuong Q. Ly; Villemure, Elisia; Pastor, Richard M.; Po-wai Yuen; Aijun Lu; Xifeng Luo; Mingcui Liu; Shun Zhang; Liang Sun; Yuhong Fu; Lupardus, Patrick J.; Wallweber, Heidi J. A.; Liederer, Bianca M.; Deshmukh, Gauri; Plise, Emile; Tay, Suzanne
Source
Subject
*DRUG design
*METHYL aspartate receptors
*ALLOSTERIC regulation
*GLYCINE
*GLUTAMATE receptors
*SYNAPSES
*THERAPEUTICS
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Language
ISSN
0022-2623
Abstract
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. [ABSTRACT FROM AUTHOR]