Introduction: - The NMDA receptor is implicated in various diseases including neurodegenerative, neurodevelopmental and mood disorders. However, only a limited number of clinically approved NMDA receptor modulators are available. Today, apparent NMDA receptor drug development strategies entail 1) exploring the unknown chemical space to identify novel scaffolds; 2) using the clinically available NMDA receptor modulators to expand the therapeutic indication space; 3) and to trace physiological functions of the NMDA receptor.
Areas covered: - The current review reflects on the functional and pharmacological facets of NMDA receptors and the current clinical status quo of NMDA receptor modulators. Patent literature covering 2015 till April 2020 is discussed with emphasis on new indications.
Expert opinion: - Supporting evidence shows that subtype-selective NMDA receptor antagonists show an improved safety profile compared to broad-spectrum channel blockers. Although GluN2B-selective antagonists are by far the most extensively investigated subtype-selective modulators, they have shown only modest clinical efficacy so far. To overcome the limitations that have hampered the clinical development of previous subtype-selective NMDA receptor antagonists, future studies with improved animal models that better reflect human NMDA receptor pathophysiology are warranted. The increased availability of subtype-selective probes will allow target engagement studies and proper dose finding in future clinical trials.
Keywords: NMDA receptor modulators; alzheimer’s; excitotoxicity; gaucher; glun2b subunits; glutamate; mood disorders; multiple sclerosis; neurodegenerative diseases; peripheral NMDA receptors; pulmonary hypertension.