Ketamine Metabolite (2R,6R)-Hydroxynorketamine Interacts with µ and κ Opioid Receptors.
ACS Chem Neurosci
; 12(9): 1487-1497, 2021 05 05.
Article
en En
| MEDLINE
| ID: mdl-33905229
ABSTRACT
Ketamine is an anesthetic, analgesic, and antidepressant whose secondary metabolite (2R,6R)-hydroxynorketamine (HNK) has N-methyl-d-aspartate-receptor-independent antidepressant activity in a rodent model. In humans, naltrexone attenuates its antidepressant effect, consistent with opioid pathway involvement. No detailed biophysical description is available of opioid receptor binding of ketamine or its metabolites. Using molecular dynamics simulations with free energy perturbation, we characterize the binding site and affinities of ketamine and metabolites in µ and κ opioid receptors, finding a profound effect of the protonation state. G-protein recruitment assays show that HNK is an inverse agonist, attenuated by naltrexone, in these receptors with IC50 values congruous with our simulations. Overall, our findings are consistent with opioid pathway involvement in ketamine function.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Ketamina
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
ACS Chem Neurosci
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos