Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
Acta Pharmacol Sin. 2019 Jun;40(6):746-754. doi: 10.1038/s41401-018-0162-z. Epub 2018 Oct 12.
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 IC of 2.9 ± 1.2 µM at - 120 mV on HCN2 channel expressed in COS7 cells. Further analysis revealed that application of compound 4e (10 μM) caused a slowing of activation and a hyperpolarizing shift (ΔV = - 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 IC of 17.2 ± 1.3 and 7.3 ± 1.2 μM, respectively. Besides, we showed that application of compound 4e (10 μM) inhibited I 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.
超极化激活环核苷酸门控 (HCN) 通道在心脏和神经系统的起搏活动控制中起着关键作用。开发 HCN 通道抑制剂被认为是治疗疼痛、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。在这项研究中，我们设计并合成了八种烷醇胺衍生物，并使用全细胞膜片钳技术评估了它们对在 COS7 细胞中表达的 HCN 通道的影响。其中，化合物 4e 在 -120 mV 时对 COS7 细胞中表达的 HCN2 通道的抑制活性最强，IC 为 2.9 ± 1.2 μM。进一步的分析表明，应用化合物 4e（10 μM）导致 HCN2 通道激活的电压依赖性减慢和超极化移位（ΔV = -30.2 ± 2.9 mV，n = 5）。化合物 4e 对在 COS7 细胞中表达的 HCN1 和 HCN4 通道的抑制作用较弱，IC 分别为 17.2 ± 1.3 和 7.3 ± 1.2 μM。此外，我们表明，应用化合物 4e（10 μM）抑制了急性分离的小鼠小背根神经节神经元中的 I 和动作电位发放。我们的研究为设计和开发强效 HCN 通道抑制剂提供了一种新策略。
