Novel dual-target FAAH and TRPV1 ligands as potential pharmacotherapeutics for pain management

Dual-acting drugs that simultaneously inhibit fatty acid amide hydrolase (FAAH) and antagonize the transient receptor potential vanilloid 1 (TRPV1) is a promising stronger therapeutic approach for pain management without side effects associated with single-target agents. Here, several series of dual FAAH/TRPV1 blockers were designed and synthesized through rational molecular hybridization between the pharmacophore of classical TRPV1 antagonists and FAAH inhibitors. The studies resulted in compound 2r, which exhibited strong dual FAAH/TRPV1 inhibition/antagonism in vitro, exerted powerful analgesic effects in formalin-induced pain test (phase II, in mice), desirable anti-inflammatory activity in carrageenan-induced paw edema in rats, no TRPV1-related hyperthermia side effect, and favorable pharmacokinetic properties. Meanwhile, the contributions of TRPV1 and FAAH to its antinociceptive effects were verified by target engagement and molecular docking studies. Overall, compound 2r can serve as a new scaffold for developing FAAH/TRPV1 dual-activie ligands to counteract pain. In order to develop dual-target FAAH and TRPV1 ligands, multiple series of dual FAAH/TRPV1 blockers were designed and synthesized through rational molecular hybridization between the pharmacophore of classical TRPV1 antagonists and FAAH inhibitors, and their in vitro and in vivo activities were evaluated. [Display omitted] •Synthesized multiple dual FAAH/TRPV1 blockers through rational hybridization of TRPV1 antagonists and FAAH inhibitors.•Compound 2r shows top dual FAAH/TRPV1 blocking in vitro, with potent analgesic and anti-inflammatory effects in vivo.•Compound 2r exhibited a good pharmacokinetic profile with no TRPV1 related hyperthermia side effects.