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, Vicent Casadó, Michael H. Baumann, Leonardo Pardo, Sergi Ferré*, Michael Michaelides*

*Autor correspondiente de este trabajo

Producción científica: Contribución a una revistaArtículoInvestigaciónrevisión exhaustiva

1 Cita (Scopus)

Resumen

(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.
Idioma originalInglés
PublicaciónMolecular Psychiatry
DOI
EstadoAceptada en prensa - 25 dic 2023

Huella

Profundice en los temas de investigación de 'Unique pharmacodynamic properties and low abuse liability of the µ-opioid receptor ligand (S)-methadone'. En conjunto forman una huella única.

Citar esto