Cardamonin, a Novel Antagonist of hTRPA1 Cation Channel, Reveals Therapeutic Mechanism of Pathological Pain

Molecules

Lianghui Ma¹  Shiyou Li²  Chenxi Zhai³  Yuxin Zhang³  Yanling Zhang³  Yangyang Yu³  Yanjiang Qiao³  Shifeng Wang³ 

[1] HD Biosciences, Co., Ltd., 590 Ruiqing Road, Zhangjiang Hi-Tech Park East Campus, Pudong New Area, Shanghai 201201, China;Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, No. 1 Beichen West Road, Chaoyang District, Beijing 100101, China;Key Laboratory of TCM-Information Engineer of State Administration of TCM, School of Chinese Materia Medica, Beijing University of Chinese Medicine, No. 6 Wangjing Zhonghuan South Road, Chaoyang District, Beijing 100102, China;

关键词: Alpinia katsumadai hayata;    cardamonin;    TRPA1 antagonist;    hyperalgeisa;    cardiotoxicity;   

DOI  :  10.3390/molecules21091145

来源: DOAJ

【 摘 要 】

The increasing demand for safe and effective treatments of chronic pain has promoted the investigation of novel analgesic drugs. Some herbals have been known to be able to relieve pain, while the chemical basis and target involved in this process remained to be clarified. The current study aimed to find anti-nociceptive candidates targeting transient receptor potential ankyrin 1 (TRPA1), a receptor that implicates in hyperalgesia and neurogenic inflammation. In the current study, 156 chemicals were tested for blocking HEK293/TRPA1 ion channel by calcium-influx assay. Docking study was conducted to predict the binding modes of hit compound with TRPA1 using Discovery Studio. Cytotoxicity in HEK293 was conducted by Cell Titer-Glo assay. Additionally, cardiotoxicity was assessed via xCELLigence RTCA system. We uncovered that cardamonin selectively blocked TRPA1 activation while did not interact with TRPV1 nor TRPV4 channel. A concentration-dependent inhibitory effect was observed with IC50 of 454 nM. Docking analysis of cardamonin demonstrated a compatible interaction with A-967079-binding site of TRPA1. Meanwhile, cardamonin did not significantly reduce HEK293 cell viability, nor did it impair cardiomyocyte constriction. Our data suggest that cardamonin is a selective TRPA1 antagonist, providing novel insight into the target of its anti-nociceptive activity.

【 授权许可】

Unknown