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
  • 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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