The N-Methyl-D-Aspartate receptor (NMDAR) is a Na+- and Ca2+- permeable ionotropic glutamate receptor that is activated by the co-agonists glycine and glutamate. NMDARs are thought to be involved in learning and memory, and their dysfunction has been implicated in a number of neurological and psychiatric disorders, including schizophrenia, depression, and Alzheimer’s disease. Recently, the identification of NMDAR positive allosteric modulators (PAMs) have appeared in the literature with the aim of targeting neural circuit dysfunction via both non-selective and subunit-selective (i.e. GluN2C/2D) PAMs. Herein we describe the discovery of potent GluN2A-selective NMDAR 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 AMPA receptors and other GluN2 subtypes. Meanwhile, the structure-activity relationship of channel deactivation kinetics was studied using a combination of automated electrophysiology and protein crystallography. These efforts culminated in the discovery of potent and selective GluN2A PAMs suitable for in vivo characterization.

Discovery of highly potent, selective, and brain-penetrant GluN2A-selective NMDA receptor positive allosteric modulators (PAMs)

251st National Meeting (2016)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.