2. Academic Validation
  3. Novel dual-target FAAH and TRPV1 ligands as potential pharmacotherapeutics for pain management

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

  • Eur J Med Chem. 2024 Mar 5:267:116208. doi: 10.1016/j.ejmech.2024.116208.
Zhenrui Qiao 1,  Shuyu Liu 2,  Weibin Zhai 1,  Lei Jiang 1,  Yunmeng Ma 1,  Zhikang Zhang 1,  Bingxin Wang 1,  Jingwen Shao 1,  Hai Qian 2,  Fenqin Zhao 3,  Lin Yan 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Antiviral Drugs, School of Pharmacy, Henan University, N. Jinming Ave., Kaifeng, Henan, 475004, China.
  • 2 State Key Laboratory of Natural Medicines, Center of Drug Discovery, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, Jiangsu, 210009, China.
  • 3 State Key Laboratory of Antiviral Drugs, School of Pharmacy, Henan University, N. Jinming Ave., Kaifeng, Henan, 475004, China. Electronic address: 10200060@vip.henu.edu.cn.
  • 4 State Key Laboratory of Antiviral Drugs, School of Pharmacy, Henan University, N. Jinming Ave., Kaifeng, Henan, 475004, China. Electronic address: yanlin@henu.edu.cn.
PMID: 38325006 DOI: 10.1016/j.ejmech.2024.116208
Abstract

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.

Keywords

Analgesic; Fatty acid amide hydrolase; Side effect; Transient receptor potential vanilloid type 1.

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