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

• Published in: Molecular psychiatry Vol. 29; no. 3; pp. 624 - 632
• Main Authors: Levinstein, Marjorie R., De Oliveira, Paulo A., Casajuana-Martin, Nil, Quiroz, Cesar, Budinich, Reece C., Rais, Rana, Rea, William, Ventriglia, Emilya N., Llopart, Natàlia, Casadó-Anguera, Verònica, Moreno, Estefanía, Walther, Donna, Glatfelter, Grant C., Weinshenker, David, Zarate, Carlos A., Casadó, Vicent, Baumann, Michael H., Pardo, Leonardo, Ferré, Sergi, Michaelides, Michael
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2024; Nature Publishing Group
• Subjects: 631/378; 64/60; 692/699/476/5; 96/33; 96/95; Agonists; Analgesia; Analgesics, Opioid - pharmacology; Animals; Behavioral Sciences; Biological Psychology; Dopamine; Dopamine - metabolism; Dopamine receptors; Enantiomers; Galanin; Glutamic acid receptors; Humans; Ligands; Male; Medicine; Medicine & Public Health; Methadone; Methadone - pharmacology; Mice; N-Methyl-D-aspartic acid receptors; Narcotics; Neurosciences; Opioid receptors; Pharmacodynamics; Pharmacotherapy; Psychiatry; Receptors, N-Methyl-D-Aspartate - metabolism; Receptors, Opioid, mu - drug effects; Receptors, Opioid, mu - metabolism; Stereoisomerism
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/s41380-023-02353-z

(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 Gal 1 receptor (Gal 1 R) 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-Gal 1 R heteromer, decreasing its abuse liability.