Esmethadone (REL-1017) and Other Uncompetitive NMDAR Channel Blockers May Improve Mood Disorders via Modulation of Synaptic Kinase-Mediated Signaling.
Stephen M Stahl, Sara de Martin, Andrea Mattarei, Ezio Bettini, Luca Pani, Clotilde Guidetti, Franco Folli, Marc De Somer, Sergio Traversa, Charles E Inturrisi, Marco Pappagallo, Marco Gentilucci, Andrea Alimonti, Maurizio Fava, Paolo L. Manfredi
International Journal of Molecular Sciences October 13, 2022 DOI: 10.3390/ijms232012196 (opens in new tab) via PubMed
Summary
AI-generated from the abstractEsmethadone (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.
Study at a glance
| Characteristics | Theoretical or philosophical paper Peer reviewed |
|---|---|
| Intervention | Esmethadone (REL-1017) |
| Topics | Depression Esketamine Ketamine Neuroplasticity |
| Keywords | N-methyl-d-aspartate receptor Rel-1017 D-methadone Dextromethorphan |
| Key finding | Proposes that esmethadone and other uncompetitive NMDAR antagonists may restore neural plasticity via preferential tonic block of hyperactive GluN2D subtypes, and that MDD may be caused by upregulated tonic Ca2+ currents through these subtypes reducing synaptic protein availability. |
Abstract
This article presents a mechanism of action hypothesis to explain the rapid antidepressant effects of esmethadone (REL-1017) and other uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonists and presents a corresponding mechanism of disease hypothesis for major depressive disorder (MDD). Esmethadone and other uncompetitive NMDAR antagonists may restore physiological neural plasticity in animal models of depressive-like behavior and in patients with MDD via preferential tonic block of pathologically hyperactive GluN2D subtypes. Tonic Ca2+ currents via GluN2D subtypes regulate the homeostatic availability of synaptic proteins. MDD and depressive behaviors may be determined by reduced homeostatic availability of synaptic proteins, due to upregulated tonic Ca2+ currents through GluN2D subtypes. The preferential activity of low-potency NMDAR antagonists for GluN2D subtypes may explain their rapid antidepressant effects in the absence of dissociative side effects.