Structural basis of opioid receptor activation by PCP and ketamine.

Summary

Using structural biology with complementary mutagenesis and SAR, the authors show ketamine and PCP directly bind and activate human opioid receptors, and report the apo structure of the human κ-opioid receptor. Distinct binding dynamics for ketamine versus PCP at the orthosteric site provide a mechanistic basis for ketamine’s unique pharmacology beyond NMDAR antagonism.

Key Findings

• Cryo-EM structures show ketamine and PCP directly bind and activate human opioid receptors.
• Site-directed mutagenesis and SAR pinpoint key recognition motifs modulating efficacy.
• Ligand-free (apo) human κ-opioid receptor structure reveals pre-engagement conformational details.
• Ketamine exhibits distinct orthosteric binding dynamics versus PCP, potentially explaining unique pharmacology.

Clinical Implications

Understanding ketamine’s opioid receptor engagement may inform perioperative dosing strategies, predict naloxone responsiveness, and guide the development of safer, biased ligands for analgesia.

Limitations

• Findings are preclinical; no direct in vivo confirmation of receptor-mediated clinical effects
• Behavioral/clinical correlates of receptor engagement were not assessed

Future Directions

Quantify opioid receptor contributions to ketamine’s analgesia and antidepressant effects in vivo; develop ligands leveraging identified motifs for safer, biased signaling; evaluate naloxone modulation in clinical trials.