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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number12196
JournalInternational Journal of Molecular Sciences
Volume23
Issue number20
DOIs
StatePublished - Oct 2022

Keywords

  • N-methyl-D-aspartate receptor
  • REL-1017
  • d-methadone
  • depression
  • dextromethorphan
  • esketamine
  • esmethadone
  • ketamine
  • major depressive disorder
  • neural plasticity

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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