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

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

  • Bioorg Chem. 2025 Jan:154:108088. doi: 10.1016/j.bioorg.2024.108088.
Yiming Qi 1,  Hao Gong 2,  Zhiya Wang 2,  Xiaoxuan Song 2,  Zixian Shen 2,  Limeng Wu 3,  Yujia Gu 2,  Weiyi Wang 4,  Xinyu Li 2,  Mingzuo Zhang 2,  Zonghe Xu 2,  Jingsong Qiu 5,  Han Wen 2,  Zihua Xu 5,  Nuo Shi 6,  Xiang Li 7,  Qingchun Zhao 8
Affiliations

Affiliations

  • 1 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.
  • 2 School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
  • 3 Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
  • 4 Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
  • 5 Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang 110840, People's Republic of China.
  • 6 College of Pharmacy, Dalian Medical University, Dalian 116044, People's Republic of China.
  • 7 Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang 110840, People's Republic of China. Electronic address: lixiangsypu@126.com.
  • 8 Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang 110840, People's Republic of China. Electronic address: zhaoqingchun1967@163.com.
PMID: 39721146 DOI: 10.1016/j.bioorg.2024.108088
Abstract

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.

Keywords

Antagonist; Cold pain; Neuropathic pain; Oxyindole; TRPA1.

Figures
Products