Design, synthesis and biological activity of pyrazolo[1,5-a]pyrimidin-7(4H)-ones as novel Kv7/KCNQ potassium channel activators |
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Authors: | Qi Jinlong Zhang Fan Mi Yi Fu Yan Xu Wen Zhang Diqun Wu Yibing Du Xiaona Jia Qingzhong Wang Kewei Zhang Hailin |
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Affiliation: | a Department of Development for New Drugs, School of Pharmacy, Hebei Medical University, Shijiazhuang 050017, China b Department of Pharmacology, Hebei Medical University, Shijiazhuang 050017, China c Department of Neurobiology and Neuroscience Research Institute, Peking University Health Science Center, Beijing 100191, China |
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Abstract: | Voltage-gated Kv7/KCNQ/M-potassium channels play a pivotal role in controlling neuronal excitability. Genetic reduction of KCNQ channel activity as a result of mutations causes various human diseases such as epilepsy and arrhythmia. Therefore, discovery of small molecules that activate KCNQ channels is an important strategy for clinical intervention of membrane excitability related disorders. In this study, a series of pyrazolo[1,5-a]pyrimidin-7(4H)-ones (PPOs) have been found to be novel activators (openers) of KCNQ2/3 potassium channels through high-throughput screening by using atomic absorption rubidium efflux assay. Based on structure-activity relationship (SAR), the substituted PPOs have been optimized. The 5-(2,6-dichloro-5-fluoropyridin-3-yl)-3-phenyl-2-(trifluoromethyl) pyrazolo[1,5-a]pyrimidin-7(4H)-one (17) was identified as a novel, potent, and selective KCNQ2/3 potassium channel opener by patch-clamp recording assay. |
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Keywords: | Pyrazolo[1,5-a]pyrimidin-7(4H)-ones Kv7/KCNQ/M-channel KCNQ2/3 channel activator Atomic absorption Rb+ efflux assay Whole-cell patch-clamp recording |
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