Department of Comprehensive Surgery, Zhengzhou People's Hospital, Zhengzhou, P. R. China.
Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, P. R. China.
Chem Biol Drug Des. 2024 Jul;104(1):e14584. doi: 10.1111/cbdd.14584.
Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel, which is considered a highly validated target for pain perception. Repeated activation with agonists to desensitize receptors or use the antagonists can both exert analgesic effects. In this work, two series of novel phenylpiperazine derivatives were designed, synthesized, and evaluated for the in vitro receptor inhibitory activity and in vivo analgesic activity. Among them, L-21 containing sulfonylurea group was identified with potent TRPV1 antagonistic activity and analgesic activity in various pain models. At the same time, L-21 exhibited low risk of hyperthermia side effect. These results indicated that L-21 is a promising candidate for further development of novel TRPV1 antagonist to treat pain.
瞬时受体电位香草酸 1 型（TRPV1）是非选择性阳离子通道，被认为是疼痛感知的高度验证靶点。用激动剂反复激活以脱敏受体或使用拮抗剂均可发挥镇痛作用。在这项工作中，设计、合成了两个系列的新型苯基哌嗪衍生物，并对其体外受体抑制活性和体内镇痛活性进行了评价。其中，含有磺酰脲基团的 L-21 被鉴定具有很强的 TRPV1 拮抗活性和各种疼痛模型的镇痛活性。同时，L-21 显示出低发热副作用的风险。这些结果表明，L-21 是进一步开发新型 TRPV1 拮抗剂治疗疼痛的有前途的候选药物。
