Advances in the Structural Basis of GluN2A-Selective Negative Allosteric Modulators

<i>N</i>-Methyl-d-aspartate receptors (NMDARs) are ligand-gated ion channels that play a critical role in synaptic plasticity, learning, and memory in the central nervous system (CNS). These receptors assemble into functionally diverse complexes composed of GluN1, GluN2, and GluN3 subunits. Among them, GluN1/GluN2A is expressed predominantly in adult brain, and its dysfunction has been implicated in various neuropathological conditions. Recent advances have identified several GluN2A-targeted agents, including highly selective negative allosteric modulators (NAMs). Structure-activity relationship (SAR) studies of existing agents have provided valuable insights into structural modifications that enhance pharmacological properties, offering promising avenues for therapeutic development.