A Novel Bifunctional OR Agonist and ₁R Antagonist with Potent Analgesic Responses and Reduced Adverse Effects

Bifunctional ligands possessing both mu OR agonism and sigma R-1 antagonism have shown promise in producing strong analgesic effects with reduced opioid-related side effects. However, the mu OR agonism activity of most dual ligands diminishes compared with classical opioids, raising concern about their effectiveness in managing nociceptive pain. In this study, a new class of dual mu OR agonist/sigma R-1 antagonist was reported. Through structure-activity relationship analyses, we identified the optimal compound, 4x, which displayed picomolar mu OR agonism activity (EC50: 0.6 +/- 0.2 nM) and good sigma R-1 inhibitory activity (K-i: 363.7 +/- 5.6 nM) with excellent selectivity. Compound 4x exhibited robust analgesic effects in various pain models, with significantly reduced side effects. Importantly, compound 4x also possessed good safety profiles and no abnormalities were observed in biological parameters even under a high dosage. Our findings suggest that 4x may be a promising lead compound for developing safer opioids and warrants further in-depth studies.