Department of Pharmacology, Shantou University Medical College, No. 22, Xinling Road, Shantou City, Guangdong Province, PR China.
Department of Pharmacology, Shantou University Medical College, No. 22, Xinling Road, Shantou City, Guangdong Province, PR China.
Pharmacol Res. 2019 Jan;139:153-157. doi: 10.1016/j.phrs.2018.11.017. Epub 2018 Nov 14.
The first clinically used antiarrhythmic, antianginal and anti-hypertensive phenylalkylamine, verapamil's cardiovascular activity is inextricably linked to its ability to antagonize Ca overload via blocking Ca1.2, a cardiac L-type Ca channel of undisputed physiological and pharmacological importance in cardiovascular disorders such as myocardial ischemia-reperfusion injury. From a structural point of view, however, the action mechanism of verapamil is still elusive. Therefore, incorporating previous findings for verapamil and Ca1.2, this review article puts forward two experimental data-derived and -supported 3D structure models for Ca1.2's α subunit and its verapamil-bound form. Furthermore, this article suggests three biophysical mechanisms, namely competitive binding, steric hindrance and electrostatic repulsion, towards an atomic level understanding of how verapamil blocks the L-type Ca current mediated by Ca1.2 in reality, which can be useful for the design and development of next-generation Ca antagonists to provide safer and more effective treatment of cardiovascular diseases.
维拉帕米是第一个临床应用的抗心律失常、抗心绞痛和抗高血压的苯烷胺类药物，其心血管活性与其通过阻断 Ca1.2 拮抗 Ca 超载的能力密切相关。Ca1.2 是一种心脏 L 型 Ca 通道，在心肌缺血再灌注损伤等心血管疾病中具有不可争议的生理和药理重要性。然而，从结构的角度来看，维拉帕米的作用机制仍然难以捉摸。因此，本文结合以前关于维拉帕米和 Ca1.2 的研究结果，提出了两种基于实验数据的 Ca1.2α亚基及其与维拉帕米结合形式的三维结构模型。此外，本文还提出了三种生物物理机制，即竞争性结合、空间位阻和静电排斥，以从原子水平上理解维拉帕米如何在实际中阻断由 Ca1.2 介导的 L 型 Ca 电流，这对于设计和开发新一代 Ca 拮抗剂以提供更安全、更有效的心血管疾病治疗可能是有用的。
