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2024-03-01

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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/226055

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

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Recurs relacionat

https://doi.org/10.1038/s41380-023-02353-z

Resum

(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.

Matèries

Opiacis, Receptors de neurotransmissors

Matèries (anglès)

Opioids, Neurotransmitter receptors

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Articles publicats en revistes (Bioquímica i Biomedicina Molecular)
Articles publicats en revistes (Institut de Biomedicina (IBUB))

Citació

WALTHER, Donna, GLATFELTER, Grant c., WEINSHENKER, David, ZARATE, Carlos a., CASADÓ, Vicent, BAUMANN, Michael h., PARDO, Leonardo, FERRÉ, Sergi, MICHAELIDES, Michael, LEVINSTEIN, Marjorie, DE OLIVEIRA, Paulo a., CASAJUANA-MARTIN, Nil, QUIROZ, César, BUDINICH, Reece c., RAIS, Rana, REA, William, VENTRIGLIA, Emilya, LLOPART, Natàlia, CASADÓ ANGUERA, Verònica, MORENO GUILLÉN, Estefanía.  Unique pharmacodynamic properties and low abuse liability of the µ-opioid receptor ligand (S)-methadone. _Molecular Psychiatry_. 2024. Vol. 29, núm. 3, pàgs. 624-632. [consulta: 28 de gener de 2026]. ISSN: 1359-4184. [Disponible a: https://hdl.handle.net/2445/226055]

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