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

Marjorie R Levinstein; Paulo A De Oliveira; Nil Casajuana-Martin; Cesar Quiroz; Reece C Budinich; Rana Rais; William Rea; Emilya N Ventriglia; Natàlia Llopart; Verònica Casadó-Anguera; Estefanía Moreno; Donna Walther; Grant C Glatfelter; David Weinshenker; Carlos A Zarate Jr; Vicent Casadó; Michael H Baumann; Leonardo Pardo; Sergi Ferré; Michael Michaelides

doi:10.1038/s41380-023-02353-z

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

Mol Psychiatry. 2023 Dec 25. doi: 10.1038/s41380-023-02353-z. Online ahead of print.

Authors

Marjorie R Levinstein^#¹, Paulo A De Oliveira^#², Nil Casajuana-Martin^#³, Cesar Quiroz², Reece C Budinich¹, Rana Rais⁴, William Rea², Emilya N Ventriglia¹, Natàlia Llopart⁵, Verònica Casadó-Anguera⁵, Estefanía Moreno⁵, Donna Walther⁶, Grant C Glatfelter⁶, David Weinshenker⁷, Carlos A Zarate Jr⁸, Vicent Casadó⁵, Michael H Baumann⁶, Leonardo Pardo³, Sergi Ferré⁹, Michael Michaelides^{10

11}

Affiliations

¹ Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, 21224, USA.
² Integrative Neurobiology Section, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, 21224, USA.
³ Laboratory of Computational Medicine, Biostatistics Unit, Faculty of Medicine, Universitat Autònoma Barcelona, Bellaterra, 08193, Barcelona, Spain.
⁴ Johns Hopkins Drug Discovery, Neurology and Pharmacology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA.
⁵ Laboratory of Molecular Neuropharmacology, Department of Biochemistry and Molecular Biomedicine, Faculty of Biology and Institut de Biomedicina de la Universitat de Barcelona, 08028, Barcelona, Spain.
⁶ Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA.
⁷ Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322, USA.
⁸ Section on the Neurobiology and Treatment of Mood Disorders, National Institute of Mental Health Intramural Research Program, Bethesda, MD, 20892, USA.
⁹ Integrative Neurobiology Section, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, 21224, USA. sergi.ferre@nih.gov.
¹⁰ Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, 21224, USA. mike.michaelides@nih.gov.
¹¹ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. mike.michaelides@nih.gov.

^# Contributed equally.

PMID: 38145984
DOI: 10.1038/s41380-023-02353-z

Abstract

(R,S)-methadone ((R,S)-MTD) is a µ-opioid receptor (MOR) agonist comprised of (R)-MTD and (S)-MTD enantiomers. (S)-MTD is being developed as an antidepressant and is considered an N-methyl-D-aspartate receptor (NMDAR) antagonist. We compared the pharmacology of (R)-MTD and (S)-MTD and found they bind to MORs, but not NMDARs, and induce full analgesia. Unlike (R)-MTD, (S)-MTD was a weak reinforcer that failed to affect extracellular dopamine or induce locomotor stimulation. Furthermore, (S)-MTD antagonized motor and dopamine releasing effects of (R)-MTD. (S)-MTD acted as a partial agonist at MOR, with complete loss of efficacy at the MOR-galanin Gal₁ 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. One-sentence summary: (S)-MTD, like (R)-MTD, binds to and activates MORs in vitro, but (S)-MTD antagonizes the MOR-Gal₁R heteromer, decreasing its abuse liability.

Grants and funding

ZIA DA000069/ImNIH/Intramural NIH HHS/United States