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)
Study at a glance
AI-extracted from the abstract| 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 Esmethadone |
| Key points | 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.