Quercetin is a natural flavonoid which has been reported to be analgesic in different animal models of pain. However, the mechanism underlying the pain-relieving effects is still unclear. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play critical roles in controlling pacemaker activity in cardiac and nervous systems, making the channel a new target for therapeutic exploration. In this study, we explored a series of flavonoids for their modulation on HCN channels. Among all tested flavonoids, quercetin was the most potent inhibitor for HCN channels with an IC₅₀ value of 27.32 ± 1.19 μM for HCN2. Furthermore, quercetin prominently left shifted the voltage-dependent activation curves of HCN channels and decelerated deactivation process. The results presented herein firstly characterize quercetin as a novel and potent inhibitor for HCN channels, which represents a novel structure for future drug design of HCN channel inhibitors.

槲皮素是一种天然的类黄酮，据报道在不同的动物疼痛模型中均具有镇痛作用。但是，减轻疼痛作用的机制尚不清楚。超极化激活的环状核苷酸门控（HCN）通道在控制心脏和神经系统中的起搏器活动中起着关键作用，使该通道成为治疗探索的新目标。在这项研究中，我们探索了一系列类黄酮对HCN通道的调节作用。在所有测试的类黄酮中，槲皮素是HCN通道最有效的抑制剂，IC ₅₀HCN2的27.32±1.19μM值。此外，槲皮素显着向左移动了HCN通道的电压依赖性激活曲线并降低了失活过程。本文呈现的结果首先将槲皮素表征为HCN通道的新型有效抑制剂，这代表了HCN通道抑制剂未来药物设计的新型结构。