Novel dual-target μ‑opioid and TRPV1 ligands as potential pharmacotherapeutics for pain management

Currently, the development of effective analgesic drugs with few side effects remains a great challenge. Studies have suggested that multi-target drug treatments show high efficacy and reduced side effects compared to single-target drug therapies. In this work, we designed and synthesized two series of novel MOR/TRPV1 dual active ligands in which the phenylpiperidine group or the N-phenyl-N-(piperidin-4-yl) propionamide group as the MOR pharmacophore was fused to the benzylpiperazinyl urea-based TRPV1 pharmacophore. In particular, compound 5a exhibited promising dual pharmacological activity for MOR (EC50 = 53.7 nM) and TRPV1 (IC50 = 32.9 nM) in vitro. In formalin tests, compound 5a showed potent, dose-dependent in vivo analgesic activity in both the 1st and 2nd phases. Gratifyingly, compound 5a did not cause the side effects of hyperthermia and analgesic tolerance. Consistent with its in vitro activity, compound 5a also simultaneously agonized MOR and antagonized TRPV1 in vivo. Further studies on compound 5a showed acceptable pharmacokinetic properties and brain permeability. Furthermore, molecular docking studies showed that compound 5a tightly bound to the active pockets of hMOR and hTRPV1, respectively. Overall, this work shows the promise in discovering new analgesic treatments through the strategy of simultaneously targeting MOR and TRPV1 with a single molecule.