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新型吡唑并[1,5-a]嘧啶-7(4H)-酮衍生物激活 KCNQ2/3 钾通道。

Activation of KCNQ2/3 potassium channels by novel pyrazolo[1,5-a]pyrimidin-7(4H)-one derivatives.

机构信息

Department of Pharmacology, Hebei Medical University, Shijiazhuang, China.

出版信息

Pharmacology. 2011;87(5-6):297-310. doi: 10.1159/000327384. Epub 2011 May 17.

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.

摘要

电压门控 M 型钾通道主要由 KCNQ2/3 基因编码,在控制神经元兴奋性方面发挥着重要作用。KCNQ2 基因突变导致一种称为“良性家族性新生儿惊厥”的人类新生儿癫痫形式,其特征是神经元过度兴奋。KCNQ 开放剂或激活剂有望降低过度活跃神经元的放电,因此有利于癫痫和疼痛的治疗。在这里,我们报告了四种新型合成的吡唑并[1,5-a]嘧啶-7(4H)-酮(PPO)衍生物,分别命名为 QO-26、QO-28、QO-40 和 QO-41,它们能强烈增强中国仓鼠卵巢细胞中表达的 KCNQ2/3 通道,并使半最大激活电压(V(1/2))向超极化方向偏移。V(1/2)呈浓度依赖性负移。这些化合物显著减缓 KCNQ2/3 通道的激活和失活动力学。构效关系研究表明,C-2 位的三氟甲基、C-3 位的苯基或萘基以及 C-5 位的三氟甲基或氯甲基对于活性是必需的。这些结果表明,这四种 PPO 衍生物作为 KCNQ2/3 通道开放剂发挥作用,为设计和开发更有效的通道开放剂提供了新的思路。

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