Ketamine Metabolite (2R,6R)-Hydroxynorketamine Interacts with μ and κ Opioid Receptors
| Autor: | Lioudmila Zoubak, Roderic G. Eckenhoff, Weiming Bu, Grace Brannigan, Alexei Yeliseev, Thomas T. Joseph, Renyu Liu, Wenzhen Lin |
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| Rok vydání: | 2021 |
| Předmět: |
Hydroxynorketamine
Physiology Cognitive Neuroscience Metabolite (2R 6R)-hydroxynorketamine Pharmacology opioid receptors Biochemistry Naltrexone 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Opioid Receptor Binding medicine Inverse agonist Ketamine free energy perturbation Receptor 030304 developmental biology 0303 health sciences Depression Receptors Opioid kappa Cell Biology General Medicine molecular dynamics Antidepressive Agents chemistry Opioid norketamine 030217 neurology & neurosurgery Research Article medicine.drug |
| Zdroj: | ACS Chemical Neuroscience |
| ISSN: | 1948-7193 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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