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

The 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.