Journal of Medicinal Chemistry p. 4680 - 4692 (2017)
Update date:2022-08-11
Topics:
Qu, Chunrong
Ding, Mingmin
Zhu, Yingmin
Lu, Yungang
Du, Juan
Miller, Melissa
Tian, Jinbin
Zhu, Jinmei
Xu, Jian
Wen, Meng
Er-Bu
Wang, Jule
Xiao, Yuling
Wu, Meng
McManus, Owen B.
Li, Min
Wu, Jilin
Luo, Huai-Rong
Cao, Zhengyu
Shen, Bing
Wang, Hongbo
Zhu, Michael X.
Hong, Xuechuan
Transient receptor potential canonical 3/6/7 (TRPC3/6/7) are highly homologous receptor-operated nonselective cation channels. Despite their physiological significance, very few selective and potent agonists are available for functional examination of these channels. Using a cell-based high throughput screening approach, a lead compound with the pyrazolopyrimidine skeleton was identified as a TRPC6 agonist. Synthetic schemes for the lead and its analogues were established, and structural-activity relationship studies were carried out. A series of potent and direct agonists of TRPC3/6/7 channels were identified, and among them, 4m-4p have a potency order of TRPC3 > C7 > C6, with 4n being the most potent with an EC50 of <20 nM on TRPC3. Importantly, these compounds exhibited no stimulatory activity on related TRP channels. The potent and selective compounds described here should be suitable for evaluation of the roles of TRPC channels in the physiology and pathogenesis of diseases, including glomerulosclerosis and cancer.
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