Controlling opioid receptor functional selectivity by targeting distinct subpockets of the orthosteric site

Elife. 2021 Feb 8:10:e56519. doi: 10.7554/eLife.56519.


Controlling receptor functional selectivity profiles for opioid receptors is a promising approach for discovering safer analgesics; however, the structural determinants conferring functional selectivity are not well understood. Here, we used crystal structures of opioid receptors, including the recently solved active state kappa opioid complex with MP1104, to rationally design novel mixed mu (MOR) and kappa (KOR) opioid receptor agonists with reduced arrestin signaling. Analysis of structure-activity relationships for new MP1104 analogs points to a region between transmembrane 5 (TM5) and extracellular loop (ECL2) as key for modulation of arrestin recruitment to both MOR and KOR. The lead compounds, MP1207 and MP1208, displayed MOR/KOR Gi-partial agonism with diminished arrestin signaling, showed efficient analgesia with attenuated liabilities, including respiratory depression and conditioned place preference and aversion in mice. The findings validate a novel structure-inspired paradigm for achieving beneficial in vivo profiles for analgesia through different mechanisms that include bias, partial agonism, and dual MOR/KOR agonism.

Keywords: GPCR bias; biochemistry; boat/chair; chemical biology; functional selectivity; mouse; safer opioids; structure-based drug design.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Analgesics / chemistry
  • Analgesics / metabolism
  • Animals
  • Binding Sites
  • Ligands
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Molecular Docking Simulation
  • Morphinans / chemistry*
  • Receptors, Opioid, kappa / chemistry*
  • Receptors, Opioid, kappa / metabolism
  • Receptors, Opioid, mu / chemistry*
  • Receptors, Opioid, mu / metabolism
  • Structure-Activity Relationship


  • 17-cyclopropylmethyl-3-hydroxy-4,5-epoxy-7,8-en-6-((3'-iodo)benzamido)morphinan
  • Analgesics
  • Ligands
  • Morphinans
  • Receptors, Opioid, kappa
  • Receptors, Opioid, mu