Synthesis and Pharmacology of a Novel μ-δ Opioid Receptor Heteromer-Selective Agonist Based on the Carfentanyl Template

J Med Chem. 2020 Nov 25;63(22):13618-13637. doi: 10.1021/acs.jmedchem.0c00901. Epub 2020 Nov 10.


In this work, we studied a series of carfentanyl amide-based opioid derivatives targeting the mu opioid receptor (μOR) and the delta opioid receptor (δOR) heteromer as a credible novel target in pain management therapy. We identified a lead compound named MP135 that exhibits high G-protein activity at μ-δ heteromers compared to the homomeric δOR or μOR and low β-arrestin2 recruitment activity at all three. Furthermore, MP135 exhibits distinct signaling profile, as compared to the previously identified agonist targeting μ-δ heteromers, CYM51010. Pharmacological characterization of MP135 supports the utility of this compound as a molecule that could be developed as an antinociceptive agent similar to morphine in rodents. In vivo characterization reveals that MP135 maintains untoward side effects such as respiratory depression and reward behavior; together, these results suggest that optimization of MP135 is necessary for the development of therapeutics that suppress the classical side effects associated with conventional clinical opioids.

Publication types

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

MeSH terms

  • Analgesics / chemical synthesis
  • Analgesics / pharmacology
  • Animals
  • Cell Line
  • Fentanyl / analogs & derivatives*
  • Fentanyl / chemical synthesis
  • Fentanyl / pharmacology
  • Humans
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pain Measurement / drug effects
  • Pain Measurement / methods
  • Rats
  • Rats, Long-Evans
  • Receptors, Opioid, delta / agonists*
  • Receptors, Opioid, delta / metabolism


  • Analgesics
  • Receptors, Opioid, delta
  • carfentanil
  • Fentanyl