Key Laboratory of External Drug Delivery System and Preparation Technology in Universities of Yunnan and Faculty of Chinese Materia Medica, Yunnan University of Chinese Medicine, Kunming, Yunnan, China.
School of Food and Drug, Shenzhen Polytechnic University, Shenzhen, Guangdong, China; State Key Laboratory of Chemical Biology and Drug Discovery and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China.
Biomed Pharmacother. 2024 Oct;179:117422. doi: 10.1016/j.biopha.2024.117422. Epub 2024 Sep 14.
Dysfunction of the Nav1.5, Cav1.2, and Kv channels could interfere with the AP and result in arrhythmias and even heart failure. We herein present a novel library of nuciferine analogs that target ion channels for the treatment of arrhythmias. Patch clamp measurements of ventricular myocytes revealed that 6a dramatically blocked both the I and I without altering the currentvoltage relationship (including the activation potential and peak potential), accelerated the inactivation of Nav and Cav channels and delayed the resurrection of these channels after inactivation. Additionally, 6a significantly decreased the APA and RMP without affecting the APD30 or APD50. The IC values of 6a against Nav1.5 and Cav1.2 were 4.98 μM and 4.62 μM, respectively. Furthermore, 6a (10 μM) blocked I, I, and I with values of 17.01 %±2.54 %, 9.09 %±2.78 %, and 11.15 %±3.52 %, respectively. Surprisingly, 6a weakly inhibited hERG channels, suggesting a low risk of proarrhythmia. The cytotoxicity evaluation of 6a with the H9c2 cell line indicated that this compound was noncytotoxic. In vivo studies suggested that these novel nuciferine analogs could shorten the time of arrhythmia continuum induced by BaCl and normalize the HR, QRS, QT and QTc interval and the R wave amplitude. Moreover, 6a dose-dependently affected aconitine-induced arrhythmias and notably improved the cumulative dosage of aconitine required to evoke VP, VT, VF and CA in rats with aconitine-induced arrhythmia. In conclusion, nuciferine analogs could be promising ion channel blockers that could be further developed into antiarrhythmic agents.
Nav1.5、Cav1.2 和 Kv 通道的功能障碍可能会干扰 AP，导致心律失常甚至心力衰竭。我们在此提出了一种新型的烟碱类似物文库，该文库针对离子通道用于治疗心律失常。心室肌细胞的膜片钳测量显示，6a 可显著阻断 I 和 I，而不改变电流-电压关系（包括激活电位和峰值电位），加速 Nav 和 Cav 通道的失活，并延迟失活后这些通道的复活。此外，6a 显著降低了 APA 和 RMP，而不影响 APD30 或 APD50。6a 对 Nav1.5 和 Cav1.2 的 IC 值分别为 4.98μM 和 4.62μM。此外，6a（10μM）阻断 I、I 和 I 的值分别为 17.01%±2.54%、9.09%±2.78%和 11.15%±3.52%。令人惊讶的是，6a 对 hERG 通道的抑制作用较弱，提示致心律失常的风险较低。用 H9c2 细胞系进行的 6a 细胞毒性评估表明，该化合物无细胞毒性。体内研究表明，这些新型烟碱类似物可以缩短 BaCl 引起的心律失常连续时间，并使 HR、QRS、QT 和 QTc 间隔以及 R 波幅度正常化。此外，6a 剂量依赖性地影响乌头碱诱导的心律失常，并显著提高乌头碱诱导心律失常大鼠中诱发 VP、VT、VF 和 CA 所需的乌头碱累积剂量。总之，烟碱类似物可能是有前途的离子通道阻滞剂，可以进一步开发为抗心律失常药物。
