Qi Yiming, Gong Hao, Wang Zhiya, Song Xiaoxuan, Shen Zixian, Wu Limeng, Gu Yujia, Wang Weiyi, Li Xinyu, Zhang Mingzuo, Xu Zonghe, Qiu Jingsong, Wen Han, Xu Zihua, Shi Nuo, Li Xiang, Zhao Qingchun
College of Pharmacy, Dalian Medical University, Dalian 116044, People's Republic of China; Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang 110840, People's Republic of China.
School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
Bioorg Chem. 2025 Jan;154:108088. doi: 10.1016/j.bioorg.2024.108088. Epub 2024 Dec 21.
Transient Receptor Potential Ankyrin 1 (TRPA1) is a non-selective cation channel involved in detecting harmful stimuli and endogenous ligands, primarily expressed in sensory neurons. Due to its role in pain and itch, TRPA1 is a potential drug target. We identified an oxindole core structure via high-throughput screening, modified it, and tested the modified compounds in vitro and in vivo. Calcium influx assays in primary dorsal root ganglion (DRG) cells and TRPA1-overexpressing HEK-293 T cells identified best compound ZQMT-10. ZQMT-10 demonstrated strong interaction with TRPA1 in the CETSA and MST assays. Oral administration of ZQMT-10 in C57BL/6J mice significantly reduced abnormal responses in the cold plate test. ZQMT-10 alleviated pain induced by AITC application on the mouse paw or by intracolonic administration, while also increasing the pain threshold and relieving persistent inflammatory pain. These results suggest ZQMT-10 as a promising TRPA1-targeted therapeutic agent.
瞬时受体电位锚蛋白1（TRPA1）是一种非选择性阳离子通道，参与检测有害刺激和内源性配体，主要表达于感觉神经元中。由于其在疼痛和瘙痒中的作用，TRPA1是一个潜在的药物靶点。我们通过高通量筛选鉴定出一种氧化吲哚核心结构，对其进行修饰，并在体外和体内对修饰后的化合物进行测试。原代背根神经节（DRG）细胞和过表达TRPA1的HEK-293 T细胞中的钙内流试验确定了最佳化合物ZQMT-10。ZQMT-10在CETSA和MST试验中显示出与TRPA1的强相互作用。在C57BL/6J小鼠中口服ZQMT-10显著降低了冷板试验中的异常反应。ZQMT-10减轻了用异硫氰酸烯丙酯涂抹小鼠爪子或结肠内给药诱导的疼痛，同时还提高了痛阈并缓解了持续性炎性疼痛。这些结果表明ZQMT-10是一种有前景的靶向TRPA1的治疗剂。
