Synthesis and biological evaluation of a peptide-remifentanil conjugate as a novel bifunctional mu/delta-opioid receptor agonist for the treatment of pain

For the treatment of pain, the design of a bifunctional mu-opioid receptor (MOR)/delta-opioid receptor (DOR) agonist is an effective strategy to seek safer opioids with higher antinociceptive efficacy and diminished adverse side effects. Herein, we describe the design, synthesis, and evaluation of a novel bivalent ligand (SW-WL-2) with a methyl 1-(3-methoxy-3-oxopropyl)-4-(phenylamino) piperidine- 4-carboxylate moiety (remifentanil derivative) covalently linked to a dermorphin-like structure (H-Dmt-N-Me-D-Ala-Aba-Gly-NH2, BVD03) at the C-terminus. Our results showed that SW-WL-2 behaved as a potent dual agonist of MOR and DOR with significant and prolonged antinociceptive effects in acute pain models in vivo. Furthermore, SW-WL-2 exhibited reduced or no opioid-like side effects such as physical dependence or respiratory depression, in contrast to an equipotent analgesic dose of morphine or BVD03. Thus, SW-WL-2 should be used as a new lead compound for the discovery of safer opioid drugs for the treatment of pain.