Synthesis and evaluation of peptide–fentanyl analogue conjugates as dual μ/δ-opioid receptor agonists for the treatment of pain

Abstract Novel peptide-fentanyl analogue conjugates were synthesized by the covalent coupling of carfentanyl derivatives to the C-terminus or N-terminus of the conformationally constrained dermorphin tetrapeptide BVD03 via a chemical linker. The carfentanyl-related analogues displayed distinct binding and functional activities at μ/δ opioid receptors (MOR/DOR) and antinociceptive effects when conjugated to the peptide. The most potent compound, SW-LJ-11, displayed mixed MOR/DOR agonist properties in the low nanomolar range and significant analgesic efficacy in vivo in four classic mouse models of pain. Interestingly, SW-LJ-11 did not exhibit any physical dependence or respiratory depression, in contrast to an equipotent analgesic dose of morphine or BVD03, indicating that the use of opioid peptide–fentanyl analogue conjugates as dual MOR/DOR agonists may be a promising strategy for obtaining safer opioids.