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

Mol Psychiatry. 2024 Mar;29(3):624-632. doi: 10.1038/s41380-023-02353-z. Epub 2023 Dec 25.

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.

MeSH terms

  • Analgesics, Opioid* / pharmacology
  • Animals
  • Dopamine / metabolism
  • Humans
  • Ligands
  • Male
  • Methadone* / pharmacology
  • Mice
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Receptors, Opioid, mu* / drug effects
  • Receptors, Opioid, mu* / metabolism
  • Stereoisomerism

Substances

  • Receptors, Opioid, mu
  • Methadone
  • Analgesics, Opioid
  • Dopamine
  • Receptors, N-Methyl-D-Aspartate
  • Ligands