Unique pharmacodynamic properties and low abuse liability of the μ-opioid receptor ligand (S)-methadone.

Autor:	Michaelides M; NIH., Levinstein M; National Institute on Drug Abuse., De Oliveira P; National Institute on Drug Abuse., Casajuana-Martin N; Universitat Autònoma Barcelona., Quiroz C; National Institute on Drug Abuse., Budinich R; National Institute on Drug Abuse., Rais R; Johns Hopkins School of Medicine., Rea W; National Institute on Drug Abuse., Ventriglia E; National Institute on Drug Abuse., Llopart N; Universitat de Barcelona., Casadó-Anguera V; Universitat de Barcelona., Moreno E; Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine of the University of Barcelona, University of Barcelona., Walther D; National Institute on Drug Abuse., Glatfelter G; National Institute on Drug Abuse., Weinshenker D, Zarate C; NIMH., Casado V; University of Barcelona., Baumann M; National Institute on Drug Abuse., Pardo L; Universitat Autonoma de Barcelona., Ferre S; National Institute on Drug Abuse.
Jazyk:	angličtina
Zdroj:	Research square [Res Sq] 2023 Mar 23. Date of Electronic Publication: 2023 Mar 23.
DOI:	10.21203/rs.3.rs-2644719/v1
Abstrakt:	(R,S)-methadone ((R,S)-MTD) is a racemic μ-opioid receptor (MOR) agonist comprised of (R)-MTD and (S)-MTD enantiomers used for the treatment of opioid use disorder (OUD) and pain. (R)-MTD is used as an OUD treatment, has high MOR potency, and is believed to mediate (R,S)-MTD's therapeutic efficacy. (S)-MTD is in clinical development as an antidepressant and is considered an N-methyl-D-aspartate receptor (NMDAR) antagonist. In opposition to this purported mechanism of action, we found that (S)-MTD does not occupy NMDARs in vivo in rats. Instead, (S)-MTD produced MOR occupancy and induced analgesia with similar efficacy as (R)-MTD. Unlike (R)-MTD, (S)-MTD was not self-administered and failed to increase locomotion or extracellular dopamine levels indicating low abuse liability. Moreover, (S)-MTD antagonized the effects of (R)-MTD in vivo and exhibited unique pharmacodynamic properties, distinct from those of (R)-MTD. Specifically, (S)-MTD acted as a MOR partial agonist with a specific loss of efficacy at the MOR-galanin 1 receptor (Gal1R) heteromer, a key mediator of the dopaminergic effects of opioids. In sum, we report novel and unique pharmacodynamic properties of (S)-MTD that are relevant to its potential mechanism of action and therapeutic use, as well as those of (R,S)-MTD. Competing Interests: MM has received research funding from AstraZeneca, Redpin Therapeutics, and Attune Neurosciences. Dr. Zarate is a full-time U.S government employee. He is listed as a coinventor on a patent for the use of ketamine in major depression and suicidal ideation. Dr. Zarate is listed as a coinventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine and other stereoisomeric dehydro and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain. Dr. Zarate is listed as co-inventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation and post-traumatic stress disorders. Dr. Zarate has assigned his patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu