title: Pyrazolopyrimidines as Potent Stimulators for Transient Receptor Potential Canonical 3/6/7 Channels.
abstract: 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 EC50of <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.
authors.affiliation: State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (MOE) and Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Wuhan University School of Pharmaceutical Sciences , Wuhan, Hubei Province 430071, China.
authors.forename: Chunrong
authors.initials: C
authors.lastname: Qu
authors.affiliation: State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (MOE) and Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Wuhan University School of Pharmaceutical Sciences , Wuhan, Hubei Province 430071, China.
authors.forename: Mingmin
authors.initials: M
authors.lastname: Ding
authors.affiliation: Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston , Houston, Texas 77030, United States.
authors.forename: Yingmin
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston , Houston, Texas 77030, United States.
authors.forename: Yungang
authors.initials: Y
authors.lastname: Lu
authors.affiliation: School of Basic Medical Sciences, Anhui Medical University , Hefei, Anhui Province 230032, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Du
authors.affiliation: Department of Neuroscience, High Throughput Biology Center and Johns Hopkins Ion Channel Center, Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.
authors.forename: Melissa
authors.initials: M
authors.lastname: Miller
authors.affiliation: Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston , Houston, Texas 77030, United States.
authors.forename: Jinbin
authors.initials: J
authors.lastname: Tian
authors.affiliation: State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (MOE) and Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Wuhan University School of Pharmaceutical Sciences , Wuhan, Hubei Province 430071, China.
authors.forename: Jinmei
authors.initials: J
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Provincial Key laboratory for TCM Evaluation and Translational Development, China Pharmaceutical University , Nanjing, Jiangsu Province 211198, China.|The International Scientist Working Station of Neuropharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai, 201203, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (MOE) and Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Wuhan University School of Pharmaceutical Sciences , Wuhan, Hubei Province 430071, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Wen
authors.affiliation: Medical College, Tibet University , Lasa, Tibet 850000, China.
authors.forename: Aga
authors.initials: A
authors.lastname: Er-Bu
authors.affiliation: Medical College, Tibet University , Lasa, Tibet 850000, China.
authors.forename: Jule
authors.initials: J
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (MOE) and Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Wuhan University School of Pharmaceutical Sciences , Wuhan, Hubei Province 430071, China.
authors.forename: Yuling
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Department of Neuroscience, High Throughput Biology Center and Johns Hopkins Ion Channel Center, Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.
authors.forename: Meng
authors.initials: M
authors.lastname: Wu
authors.affiliation: Department of Neuroscience, High Throughput Biology Center and Johns Hopkins Ion Channel Center, Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.
authors.forename: Owen B
authors.initials: OB
authors.lastname: McManus
authors.affiliation: Department of Neuroscience, High Throughput Biology Center and Johns Hopkins Ion Channel Center, Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: The International Scientist Working Station of Neuropharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai, 201203, China.|University of Chinese Academy of Sciences , Beijing, 100049, China.
authors.forename: Jilin
authors.initials: J
authors.lastname: Wu
authors.affiliation: Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences , Kunming, Yunnan Province 650201, China.
authors.forename: Huai-Rong
authors.initials: HR
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Provincial Key laboratory for TCM Evaluation and Translational Development, China Pharmaceutical University , Nanjing, Jiangsu Province 211198, China.
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Cao
authors.affiliation: School of Basic Medical Sciences, Anhui Medical University , Hefei, Anhui Province 230032, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Shen
authors.affiliation: School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University , Yantai, Shangdong Province 264005, China.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston , Houston, Texas 77030, United States.|The International Scientist Working Station of Neuropharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai, 201203, China.
authors.forename: Michael X
authors.initials: MX
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (MOE) and Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Wuhan University School of Pharmaceutical Sciences , Wuhan, Hubei Province 430071, China.|Medical College, Tibet University , Lasa, Tibet 850000, China.
authors.forename: Xuechuan
authors.identifier: 0000-0001-6834-3278
authors.initials: X
authors.lastname: Hong
mesh_terms: D057809:HEK293 Cells; D006801:Humans; D011720:Pyrazoles / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D050052:TRPC Cation Channels / Q000819:agonists*; D000074287:TRPC6 Cation Channel
chemical_list: D011720:Pyrazoles; D011743:Pyrimidines; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; D000074287:TRPC6 Cation Channel; C117032:TRPC6 protein, human; C498501:TRPC7 protein, human