Abstract：
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.
摘要：
瞬时受体电位香草酸1（TRPV1）是一种非选择性阳离子通道，这被认为是疼痛感知的高度验证目标。用激动剂重复激活以使受体脱敏或使用拮抗剂均可发挥镇痛作用。在这项工作中,设计了两个系列的新型苯基哌嗪衍生物，合成，并评价了体外受体抑制活性和体内镇痛活性。其中,在各种疼痛模型中,含有L-21的磺酰脲组经鉴定具有有效的TRPV1拮抗活性和镇痛活性。同时,L-21表现出低的高热副作用风险。这些结果表明L-21是进一步开发新型TRPV1拮抗剂以治疗疼痛的有希望的候选物。
