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

doi:10.3390/ijms232012196

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 journal › Article › peer-review

8 Scopus citations

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 language	English (US)
Article number	12196
Journal	International Journal of Molecular Sciences
Volume	23
Issue number	20
DOIs	https://doi.org/10.3390/ijms232012196
State	Published - Oct 2022
Externally published	Yes

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

Access to Document

10.3390/ijms232012196

Cite this

Stahl, S. M., De Martin, S., Mattarei, A., Bettini, E., Pani, L., Guidetti, C., Folli, F., de Somer, M., Traversa, S., Inturrisi, C. E., Pappagallo, M., Gentilucci, M., Alimonti, A., Fava, M., & Manfredi, P. L. (2022). 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, 23(20), Article 12196. https://doi.org/10.3390/ijms232012196

Stahl, SM, De Martin, S, Mattarei, A, Bettini, E, Pani, L, Guidetti, C, Folli, F, de Somer, M, Traversa, S, Inturrisi, CE, Pappagallo, M, Gentilucci, M, Alimonti, A, Fava, M & Manfredi, PL 2022, '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, vol. 23, no. 20, 12196. https://doi.org/10.3390/ijms232012196

@article{630d0ec7504d4284a95d36a78693a78d,

title = "Esmethadone (REL-1017) and Other Uncompetitive NMDAR Channel Blockers May Improve Mood Disorders via Modulation of Synaptic Kinase-Mediated Signaling",

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.",

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

author = "Stahl, {Stephen M.} and {De Martin}, Sara and Andrea Mattarei and Ezio Bettini and Luca Pani and Clotilde Guidetti and Franco Folli and {de Somer}, Marc and Sergio Traversa and Inturrisi, {Charles E.} and Marco Pappagallo and Marco Gentilucci and Andrea Alimonti and Maurizio Fava and Manfredi, {Paolo L.}",

note = "Publisher Copyright: {\textcopyright} 2022 by the authors.",

year = "2022",

month = oct,

doi = "10.3390/ijms232012196",

language = "English (US)",

volume = "23",

journal = "International Journal of Molecular Sciences",

issn = "1661-6596",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "20",

}

TY - JOUR

T1 - Esmethadone (REL-1017) and Other Uncompetitive NMDAR Channel Blockers May Improve Mood Disorders via Modulation of Synaptic Kinase-Mediated Signaling

AU - Stahl, Stephen M.

AU - De Martin, Sara

AU - Mattarei, Andrea

AU - Bettini, Ezio

AU - Pani, Luca

AU - Guidetti, Clotilde

AU - Folli, Franco

AU - de Somer, Marc

AU - Traversa, Sergio

AU - Inturrisi, Charles E.

AU - Pappagallo, Marco

AU - Gentilucci, Marco

AU - Alimonti, Andrea

AU - Fava, Maurizio

AU - Manfredi, Paolo L.

PY - 2022/10

Y1 - 2022/10

N2 - 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.

AB - 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.

KW - N-methyl-D-aspartate receptor

KW - REL-1017

KW - d-methadone

KW - depression

KW - dextromethorphan

KW - esketamine

KW - esmethadone

KW - ketamine

KW - major depressive disorder

KW - neural plasticity

UR - http://www.scopus.com/inward/record.url?scp=85140818946&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85140818946&partnerID=8YFLogxK

U2 - 10.3390/ijms232012196

DO - 10.3390/ijms232012196

M3 - Article

C2 - 36293063

AN - SCOPUS:85140818946

SN - 1661-6596

VL - 23

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

IS - 20

M1 - 12196

ER -

Esmethadone (REL-1017) and Other Uncompetitive NMDAR Channel Blockers May Improve Mood Disorders via Modulation of Synaptic Kinase-Mediated Signaling

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this