G protein signaling-biased mu opioid receptor agonists that produce sustained G protein activation are noncompetitive agonists

Proc Natl Acad Sci U S A. 2021 Nov 30;118(48):e2102178118. doi: 10.1073/pnas.2102178118.


The ability of a ligand to preferentially promote engagement of one signaling pathway over another downstream of GPCR activation has been referred to as signaling bias, functional selectivity, and biased agonism. The presentation of ligand bias reflects selectivity between active states of the receptor, which may result in the display of preferential engagement with one signaling pathway over another. In this study, we provide evidence that the G protein-biased mu opioid receptor (MOR) agonists SR-17018 and SR-14968 stabilize the MOR in a wash-resistant yet antagonist-reversible G protein-signaling state. Furthermore, we demonstrate that these structurally related biased agonists are noncompetitive for radiolabeled MOR antagonist binding, and while they stimulate G protein signaling in mouse brains, partial agonists of this class do not compete with full agonist activation. Importantly, opioid antagonists can readily reverse their effects in vivo. Given that chronic treatment with SR-17018 does not lead to tolerance in several mouse pain models, this feature may be desirable for the development of long-lasting opioid analgesics that remain sensitive to antagonist reversal of respiratory suppression.

Keywords: allostery; biased agonism; efficacy; naloxone; tolerance.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analgesics, Opioid / pharmacology
  • Animals
  • Benzimidazoles / pharmacology
  • GTP-Binding Proteins / metabolism
  • Ligands
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Narcotic Antagonists / pharmacology
  • Piperidines / pharmacology
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, G-Protein-Coupled / physiology
  • Receptors, Opioid, mu / agonists
  • Receptors, Opioid, mu / metabolism*
  • Receptors, Opioid, mu / physiology
  • Signal Transduction / drug effects*
  • Signal Transduction / physiology
  • beta-Arrestin 2 / metabolism


  • Analgesics, Opioid
  • Benzimidazoles
  • Ligands
  • Narcotic Antagonists
  • Piperidines
  • Receptors, G-Protein-Coupled
  • Receptors, Opioid, mu
  • beta-Arrestin 2
  • sr-17018
  • GTP-Binding Proteins