AbstractN-methyl-D-aspartate (NMDA) receptors are glutamate-gated ion channels that are ubiquitously expressed throughout the central nervous system (CNS) and serve as crucial mediators of neural development and synaptic plasticity. Dysregulation of NMDA receptor activity has been implicated in a wide spectrum of neurological and psychiatric disorders. In recent years, substantial progress has been made in the clinical development of small-molecule modulators targeting NMDA receptors. In this review, we summarize recent advances in this rapidly evolving field. Among various therapeutic indications, depression has emerged as an especially active area of investigation, with mechanistically diverse compounds ranging from broad-spectrum channel blockers (ketamine, dextromethorphan, esmethadone) to glycine site modulators (rapastinel, 4-chlorokynurenine, D-cycloserine) and allosteric modulators (apimostinel, zelquistinel), progressing through clinical pipelines. Beyond depression, NMDA receptor-targeted drug discovery is also advancing in other challenging CNS disorders, including neurodegenerative diseases (salzanemdor, NYX-458), pain (NYX-2925), epilepsy (radiprodil), and stroke (nelonemdaz, NP10679). Collectively, these developments reflect the maturation of NMDA receptor pharmacology and reaffirm the broad therapeutic potential of NMDA receptor modulation, while highlighting promising directions for future drug discovery. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution Access options Access through your institution Subscribe to this journal Receive 12 print issues and online access $259.00 per year only $21.58 per issue Learn more Buy this article Purchase on SpringerLink Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated during checkout Additional access options: Log in Learn about institutional subscriptions Read our FAQs Contact customer support Fig. 1: Subunit, subtype, and expression diversity of NMDA receptors.Fig. 2: Structural mapping of binding pockets and interaction modes of representative NMDA receptor modulators. ReferencesHunt DL, Ca
