Ketamine Metabolite (2 R,6 R)-Hydroxynorketamine Interacts with μ and κ Opioid Receptors

Thomas T. Joseph, Weiming Bu, Wenzhen Lin, Lioudmila Zoubak, Alexei Yeliseev, Renyu Liu, Roderic G. Eckenhoff, Grace Brannigan

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1487-1497
Number of pages11
JournalACS Chemical Neuroscience
Issue number9
StatePublished - May 5 2021
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology


  • (2 R,6 R)-hydroxynorketamine
  • Ketamine
  • free energy perturbation
  • molecular dynamics
  • norketamine
  • opioid receptors


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