化学
止痛药
TRPV1型
药理学
对偶(语法数字)
班级(哲学)
药物发现
生物化学
受体
医学
艺术
文学类
人工智能
瞬时受体电位通道
计算机科学
作者
Chunxia Liu,Wenxin Wang,Shiyu Zhao,Siliang Chen,Haoyang Chen,Suhua Wang,Zheng Li,Hai Qian,Xin Tian
标识
DOI:10.1016/j.bmc.2024.117750
摘要
Analgesia and blood sugar control are considered as two main unmet clinical needs for diabetes related neuropathic pain patients. Transient receptor potential vanilloid type-1 (TRPV1) channel is a highly validated target for pain perception, while no TRPV1 antagonists have been approved due to hyperthermia side effects. Herein, two series of new TRPV1 antagonists with flavonoid skeleton were designed by the structure-based drug design (SBDD) strategy. After comprehensive evaluation, compound CX-3 was identified as a promising TRPV1 antagonist. CX-3 exhibited equivalent TRPV1 antagonistic activity with classical TRPV1 antagonist BCTC in vitro, and exerted better analgesic activity in vivo than that of BCTC in the formalin induced inflammatory pain model without hyperthermia risk. Moreover, CX-3 exhibited robust glucose-lowering effects and showed high selectivity over other ion channels. Overall, these findings identified a first-in-class highly selective TRPV1 antagonist CX-3, which is a promising candidate to target the pathogenesis of diabetes related neuropathic pain.
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