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

(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 bin...

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Detalles Bibliográficos
Autores: 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
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2024
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/226055
Acceso en línea:https://hdl.handle.net/2445/226055
Access Level:acceso abierto
Palabra clave:Opiacis
Receptors de neurotransmissors
Opioids
Neurotransmitter receptors
Descripción
Sumario:(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.

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