Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 46, Issue 3, Pages 934-943Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2011.01.010
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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Funding
- National Natural Science Foundation of China [30730031, 30500112]
- National Basic Research Program [2007CB512100]
- National 863 project [2006AA02Z183]
- National Science Fund for Distinguished Young Scholars of China [30325038]
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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. (C) 2011 Elsevier Masson SAS. All rights reserved.
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