jm5b02010_si_002.csv (2.68 kB)
Discovery of GluN2A-Selective NMDA Receptor Positive Allosteric Modulators (PAMs): Tuning Deactivation Kinetics via Structure-Based Design
dataset
posted on 2016-02-26, 00:00 authored by 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. SchwarzThe 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.
