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Papers of the Week

Papers: 23 Dec 2023 - 29 Dec 2023

2023 Dec 25

Mol Psychiatry


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


Levinstein MR, De Oliveira PA, Casajuana-Martin N, Quiroz C, Budinich RC, Rais R, Rea W, Ventriglia EN, Llopart N, Casadó-Anguera V, Moreno E, Walther D, Glatfelter GC, Weinshenker D, Zarate CA, Casadó V, Baumann MH, Pardo L, Ferré S, Michaelides M


(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 receptor (GalR) 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-GalR heteromer, decreasing its abuse liability.