Esmethadone (REL-1017) and Other Uncompetitive NMDAR Channel Blockers May Improve Mood Disorders via Modulation of Synaptic Kinase-Mediated Signaling.
International journal of molecular sciences October 13, 2022 Stephen M Stahl, Sara De Martin, Andrea Mattarei et al.
Esmethadone (REL-1017) and other uncompetitive NMDAR antagonists may rapidly relieve depression by preferentially blocking hyperactive GluN2D subtypes, restoring physiological neural plasticity. In major depressive disorder, upregulated tonic calcium currents through GluN2D subtypes reduce homeostatic availability of synaptic proteins, contributing to depressive behaviors. Low-potency NMDAR antagonists' selectivity for GluN2D may explain their rapid antidepressant effects without dissociative side effects.