Bias Factor and Therapeutic Window Correlate to Predict Safer Opioid Analgesics

Cell. 2017 Nov 16;171(5):1165-1175.e13. doi: 10.1016/j.cell.2017.10.035.


Biased agonism has been proposed as a means to separate desirable and adverse drug responses downstream of G protein-coupled receptor (GPCR) targets. Herein, we describe structural features of a series of mu-opioid-receptor (MOR)-selective agonists that preferentially activate receptors to couple to G proteins or to recruit βarrestin proteins. By comparing relative bias for MOR-mediated signaling in each pathway, we demonstrate a strong correlation between the respiratory suppression/antinociception therapeutic window in a series of compounds spanning a wide range of signaling bias. We find that βarrestin-biased compounds, such as fentanyl, are more likely to induce respiratory suppression at weak analgesic doses, while G protein signaling bias broadens the therapeutic window, allowing for antinociception in the absence of respiratory suppression.

Keywords: G protein-coupled receptor (GPCR); biased agonism; fentanyl; functional selectivity; morphine; mu opioid receptor; pain; respiration; side effects; βarrestin.

MeSH terms

  • Analgesics, Opioid / administration & dosage*
  • Analgesics, Opioid / adverse effects*
  • Animals
  • Fentanyl / administration & dosage
  • GTP-Binding Proteins / metabolism
  • Mice
  • Morphine / administration & dosage
  • Receptors, Opioid, mu / agonists*
  • Receptors, Opioid, mu / chemistry
  • Respiratory System / drug effects
  • Signal Transduction
  • beta-Arrestins / metabolism


  • Analgesics, Opioid
  • Receptors, Opioid, mu
  • beta-Arrestins
  • Morphine
  • GTP-Binding Proteins
  • Fentanyl