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Bifunctional ligands possessing both μOR agonism and σ 1 R antagonism have shown promise in producing strong analgesic effects with reduced opioid-related side effects. However, the μOR 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 μOR agonist/σ 1 R antagonist was reported. Through structure-activity relationship analyses, we identified the optimal compound, 4x , which displayed picomolar μOR agonism activity (EC 50 : 0.6 ± 0.2 nM) and good σ 1 R 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.

Human dihydroorotate dehydrogenase ( h DHODH) is an attractive target for cancer therapy. Based on its crystal structure, we designed and synthesized a focused compound library containing the structural moiety of 1,4-benzoquinone, which possesses reactive oxygen species (ROS) induction capacity. Compound 3s with a naphtho[2,3- d ][1,2,3]triazole-4,9-dione scaffold exhibited inhibitory activity against h DHODH. Further optimization led to compounds 11k and 11l , which inhibited h DHODH activity with IC 50 values of 9 and 4.5 nM, respectively. Protein-ligand cocrystal structures clearly depicted hydrogen bond and hydrophobic interactions of 11k and 11l with h DHODH. Compounds 11k and 11l significantly inhibited leukemia cell and solid tumor cell proliferation and induced ROS production, mitochondrial dysfunction, apoptosis, and cell cycle arrest. Nanocrystallization of compound 11l displayed significant in vivo antitumor effects in the Raji xenograft model. Overall, this study provides a novel bifunctional compound 11l with h DHODH inhibition and ROS induction efficacy, which represents a promising anticancer lead worthy of further exploration.