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

Zhenrui Qiao, Shuyu Liu, Weibin Zhai, Lei Jiang, Yunmeng Ma, Zhikang Zhang, Bingxin Wang, Jingwen Shao, Hai Qian, Fenqin Zhao, Lin Yan

European journal of medicinal chemistry 2024 Mar 05

filter terms:

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. Copyright © 2024 Elsevier Masson SAS. All rights reserved.

Citation

Zhenrui Qiao, Shuyu Liu, Weibin Zhai, Lei Jiang, Yunmeng Ma, Zhikang Zhang, Bingxin Wang, Jingwen Shao, Hai Qian, Fenqin Zhao, Lin Yan. Novel dual-target FAAH and TRPV1 ligands as potential pharmacotherapeutics for pain management. European journal of medicinal chemistry. 2024 Mar 05;267:116208