Identification and characterization of a series of novel HCN channel inhibitors
Identification and characterization of a series of novel HCN channel inhibitors
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一系列新型 HCN 通道抑制剂的鉴定和表征。
DOI：
10.1038/s41401-018-0162-z
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发表时间：
2019-06-01
影响因子：
8.2
通讯作者：
Zhou, Ping-zheng
中科院分区：
文献类型：
--
作者：
Chen, Shu-jun;Xu, Yao;Zhou, Ping-zheng
超极化激活的环核苷酸门控（HCN）通道在控制心脏和神经系统的起搏器活动中起着关键作用。开发HCN通道抑制剂已被认为是治疗疼痛、心力衰竭、心律失常和癫痫的重要策略。一种HCN通道抑制剂伊伐布雷定已被临床批准用于治疗心绞痛和心力衰竭。在本研究中，我们设计并合成了8种烷醇胺衍生物，并利用全细胞膜片钳法评估了它们对COS7细胞中HCN通道表达的影响。其中化合物4e对COS7细胞中表达的HCN2通道抑制活性最强，在-120 mV下IC50为2.9 +/- 1.2 μ M。进一步分析表明，化合物4e （10 μ M）的应用导致HCN2通道激活的电压依赖性减慢和超极化位移（Delta V-1/2 = -30.2 +/- 2.9 mV, n = 5）。化合物4e对COS7细胞中表达的HCN1和HCN4通道的抑制作用较弱，IC50分别为17.2 +/- 1.3和7.3 +/- 1.2 μ M。此外，我们发现化合物4e （10 μ M）的应用抑制了急性游离小鼠小背根神经节神经元的I-h和动作电位放电。我们的研究为设计和开发有效的HCN通道抑制剂提供了一种新的策略。
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play a critical role in controlling pacemaker activity in both heart and nervous system. Developing HCN channel inhibitors has been proposed to be an important strategy for the treatment of pain, heart failure, arrhythmias, and epilepsy. One HCN channel inhibitor, ivabradine, has been clinically approved for the treatment of angina pectoris and heart failure. In this study, we designed and synthesized eight alkanol amine derivatives, and assessed their effects on HCN channels expressed in COS7 cells using a whole-cell patch clamp method. Among them, compound 4e displayed the most potent inhibitory activity with an IC50 of 2.9 +/- 1.2 mu M at -120 mV on HCN2 channel expressed in COS7 cells. Further analysis revealed that application of compound 4e (10 mu M) caused a slowing of activation and a hyperpolarizing shift (Delta V-1/2 = -30.2 +/- 2.9 mV, n = 5) in the voltage dependence of HCN2 channel activation. The inhibitory effect of compound 4e on HCN1 and HCN4 channel expressed in COS7 cells was less potent with IC50 of 17.2 +/- 1.3 and 7.3 +/- 1.2 mu M, respectively. Besides, we showed that application of compound 4e (10 mu M) inhibited I-h and action potential firing in acutely dissociated mouse small dorsal root ganglion neurons. Our study provides a new strategy for the design and development of potent HCN channel inhibitors.