Esmethadone-HCl (REL-1017): a promising rapid antidepressant.

"structures of the complexes between esmethadone (light blue) arketamine (magenta) and esketamine (purple) with nr1-2d in the open conformation model (pdb code 6wht) and the closed conformation model (pdb code 6whs) can be seen in panels ( b-d ) and ( e-g ) [ ] table 1 in vitro and in vivo preclinical studies with esmethadone author (year) and study title objective results bettini et al (2022) pharmacological comparative characterization of rel-1017 (esmethadone-hcl) and other nmdar channel blockers in human heterodimeric n-methyl-d-aspartate receptors to characterize rel-1017 (esmethadone-hcl) and nmdars in silico and together with dextromethorphan memantine (?)-ketamine and mk-801 in cell lines over-expressing nmdar subtypes using a fluorometric imaging plate reader automated patch-clamp and manual patch-clamp electrophysiology the pharmacological characteristics of rel-1017 at nmdars included relatively low affinity at the nmdar nr1-2d subtype preference in the presence of 1 mm mg 2+ trapping similar to (?)-ketamine and preferential docking and undocking of the open nmdar bettini et al (2022) the n-methyl-d-aspartate receptor blocker rel-1017 (esmethadone) reduces calcium influx induced by glutamate quinolinic acid and gentamicin to study the effects of quinolinic acid and gentamicin with or without l-glutamate and rel-1017 on intracellular calcium ([ca 2+ ] in ) influx using the fluorometric imaging plate reader assays in recombinant cell lines expressing human glun1-glun2a glun1-glun2b glun1-glun2c and glun1-glun2d nmdar subtypes rel-1017 reduced [ca 2+ ] in induced by l-glutamate alone and when increased by quinolinic acid and gentamicin."

"Declarations Conflict of interestRelmada Therapeutics and its consultants and employees contributed to all aspects of this manuscript, including all described experimental work.  Ethical approvalNot applicable. Consent for publicationNot applicable. Conflict of interest Relmada Therapeutics and its consultants and employees contributed to all aspects of this manuscript, including all described experimental work. "

"Funding This research was sponsored by Relmada Therapeutics, Inc., Coral Gables, FL, USA. Maurizio Fava—Dr. Fava is employed by or has received compensation from companies or institutions that received funding from Relmada Therapeutics. Stephen M. Stahl—Dr. Stahl has received compensation from Relmada Therapeutics as a consultant. Sara De Martin—Dr. De Martin has received grant support from MGGM LLC and consultation fees from Neuroarbor LLC and is employed by or has received compensation from companies or institutions that received funding from Relmada Therapeutics. Andrea Mattarei—Dr. Mattarei has received grant support from MGGM LLC and consultation fees from Neuroarbor LLC and is employed by or has received compensation from companies or institutions that received funding from Relmada Therapeutics. Ezio Bettini—Dr. Bettini is employed by or has received compensation from companies or institutions that received funding from Relmada Therapeutics. Stefano Comai—Dr. Comai has received grant support from MGGM LLC and is employed by or has received compensation from companies or institutions receiving funding from Relmada Therapeutics. Andrea Alimonti—Dr. Alimonti is employed by or has received compensation from companies or institutions that received funding from Relmada Therapeutics, has received research funding from MGGM LLC, and is inventor on patent n. WO2020181194A1. Francesco Bifari—No disclosures. Luca Pani—Dr. Pani has received compensation from Relmada Therapeutics as a consultant. Franco Folli—Dr. Folli has received consultant fees from Relmada Therapeutics. Clotilde Guidetti—Dr. Guidetti has received grant support from Relmada Therapeutics and personal fees from MGGM LLC and is employed by or has received compensation from companies or institutions that received funding from Relmada Therapeutics. Alberto Furlan—Dr. Furlan is employed by or has received compensation from companies or institutions that received funding from Relmada Therapeutics. Jacopo Sgrignani—Dr. Sgrignani is employed by the Institute for Research in Biomedicine (IRB) in Bellinzona, Switzerland, which has received funding from Relmada Therapeutics. Patrizia Locatelli—Dr. Locatelli is employed by the Institute for Research in Biomedicine (IRB) in Bellinzona, Switzerland, which has received funding from Relmada Therapeutics. Andrea Cavalli—Dr. Cavalli is associated with the Swiss Institute of Bioinformatics (SIB) and The Italian Institute for Technology (IIT), both of which receive funding from Relmada Therapeutics. Cedric O’Gorman—Dr. O’Gorman is employed by Relmada Therapeutics. Sergio Traversa—Dr. Traversa is employed by Relmada Therapeutics. Charles E. Inturrisi—Dr. Inturrisi has received compensation from Relmada Therapeutics as a consultant and is an inventor on patents related to esmethadone. Marco Pappagallo—Dr. Pappagallo has received compensation from Relmada Therapeutics as a consultant. Paolo L. Manfredi—Dr. Manfredi has received compensation from Relmada Therapeutics as a consultant and is an inventor on patents related to esmethadone."