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

(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.