Discovery of novel oxindole derivatives as TRPA1 antagonists with potent analgesic activity for pain treatment.

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.