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. Epub 2016 Mar 8.


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.

MeSH terms

  • Animals
  • CHO Cells
  • Calcium / metabolism
  • Cricetinae
  • Cricetulus
  • Crystallography, X-Ray
  • Drug Discovery
  • Excitatory Amino Acid Antagonists / chemical synthesis*
  • Excitatory Amino Acid Antagonists / pharmacology*
  • HEK293 Cells
  • High-Throughput Screening Assays
  • Humans
  • Kinetics
  • Models, Molecular
  • Patch-Clamp Techniques
  • Receptors, AMPA / drug effects
  • Receptors, N-Methyl-D-Aspartate / drug effects*
  • Structure-Activity Relationship


  • Excitatory Amino Acid Antagonists
  • Receptors, AMPA
  • Receptors, N-Methyl-D-Aspartate
  • Calcium
  • N-methyl D-aspartate receptor subtype 2A