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. 2016 Mar 24;59(6):2760-79.
doi: 10.1021/acs.jmedchem.5b02010. Epub 2016 Mar 8.

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

Matthew Volgraf, Benjamin D Sellers, Yu Jiang  1 , Guosheng Wu  1 , Cuong Q Ly, Elisia Villemure, Richard M Pastor, Po-wai Yuen  1 , Aijun Lu  1 , Xifeng Luo  1 , Mingcui Liu  1 , Shun Zhang  1 , Liang Sun  1 , Yuhong Fu  1 , 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  2 , Matthias G A Dietz  2 , Yanzhou Liu, Tzu-Ming Wang, Jesse E Hanson, David Hackos, Kimberly Scearce-Levie, Jacob B Schwarz
Affiliations

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

Matthew Volgraf et al. J Med Chem. .

Abstract

The N-methyl-D-aspartate receptor (NMDAR) is a Na(+) and Ca(2+) 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.

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