title: Activation of KCNQ2/3 potassium channels by novel pyrazolo[1,5-a]pyrimidin-7(4H)-one derivatives.
abstract: The voltage-gated M-type potassium channel, encoded mainly by the KCNQ2/3 genes, plays an important role in the control of neuronal excitability. Mutations in the KCNQ2 gene lead to a form of neonatal epilepsy in humans termed 'benign familial neonatal convulsions', which is characterized by hyperexcitability of neurons. KCNQ openers or activators are expected to decrease the firing of overactive neurons and are thus conducive to the treatment of epilepsy and pain. Here, we report that four novel synthesized derivatives of pyrazolo[1,5-a]pyrimidin-7(4H)-one (PPO) named QO-26, QO-28, QO-40 and QO-41 potently augmented KCNQ2/3 channels expressed in Chinese hamster ovary cells and shifted the half-maximal activation voltage (V(1/2)) in the hyperpolarizing direction. The V(1/2) was negatively shifted in a concentration-dependent manner. The compounds markedly slowed both KCNQ2/3 channel activation and deactivation kinetics. Structure-activity relationship studies suggest that trifluoromethyl at the C-2 position, phenyl or naphthyl at the C-3 position, and trifluoromethyl or chloromethyl at the C-5 position are essential for the activity. These results suggest the four PPO derivatives act as KCNQ2/3 channel openers, providing a new dimension for the design and development of more potent channel openers.
authors.affiliation: Department of Pharmacology, Hebei Medical University, Shijiazhuang, China.
authors.forename: Caixia
authors.initials: C
authors.lastname: Jia
authors.forename: Jinlong
authors.initials: J
authors.lastname: Qi
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.forename: Yi
authors.initials: Y
authors.lastname: Mi
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhang
authors.forename: Xingjuan
authors.initials: X
authors.lastname: Chen
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Xiaona
authors.initials: X
authors.lastname: Du
authors.forename: Hailin
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D051658:KCNQ2 Potassium Channel / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D051659:KCNQ3 Potassium Channel / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; D011720:Pyrazoles; D011743:Pyrimidines; D011744:Pyrimidinones; C527752:pyrazolo(1,5-a)pyrimidine