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

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

  • J Med Chem. 2016 Mar 24;59(6):2760-79. doi: 10.1021/acs.jmedchem.5b02010.
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

Affiliations

  • 1 Pharmaron-Beijing Co. Ltd. , 6 Taihe Road, BDA, Beijing 100176, PR China.
  • 2 Ion Channels Group, Evotec AG ; Manfred Eigen Campus, Essener Bogen 7, 22419 Hamburg, Germany.
PMID: 26919761 DOI: 10.1021/acs.jmedchem.5b02010
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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