从普罗帕酮类似物中开发新的 Kir2.1 通道开启剂。

IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Encan Li, Najla Boujeddaine, Marien J C Houtman, Renee G C Maas, Joost P G Sluijter, Gerhard F Ecker, Anna Stary-Weinzinger, Willem B van Ham, Marcel A G van der Heyden
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引用次数: 0

摘要

背景和目的:内向整流钾通道(Kir2.1)功能降低与心力衰竭有关,并可能导致以室性心律失常为特征的安德森-塔维尔综合征(Andersen-Tawil Syndrome)。大多数心力衰竭或安德森-塔维尔综合征患者都接受过β肾上腺素受体拮抗剂(β-受体阻滞剂)或钠通道阻滞剂治疗,但这些药物并不专门针对内向整流电流(IK1),也不旨在改善静息膜电位的稳定性。因此,针对心力衰竭和安德森-塔维尔综合征治疗的额外药物疗法是非常可取的。低浓度的急性普罗帕酮治疗可增强 IK1 电流,但也会产生许多脱靶效应。因此,有必要发现和探索新的 IK1 通道开放剂:实验方法:分析了普罗帕酮和另外 10 种普罗帕酮类似物的作用。电流通过单细胞膜片钳电生理学测量。通过Western印迹分析确定了Kir2.1蛋白的表达水平,并在人类诱导多能干细胞衍生的心肌细胞(hiPSC-CMCs)中进一步验证了动作电位特征。通过分子对接获得了药物与通道相互作用的详细信息:主要结果:类似物 GPV0019、GPV0057 和 GPV0576 能强烈增加 IK1 的外向成分,同时不影响 Kir2.1 通道的表达水平。GPV0057 在浓度低于 0.5 μmol L-1 时不会阻断 IKr,在浓度低于 1 μmol L-1 时也不会阻断 NaV1.5 电流。此外,在 0.5 和 1 μmol L-1 浓度下,hiPSC-CMC 的动作电位持续时间也不受 GPV0057 的影响。结构分析表明了 GPV0057 可增强 Kir2.1 通道活化的机制:GPV0057 对增加 IK1 有很强的效率,这使其成为解决 IK1 缺乏相关疾病的一个很好的候选药物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Development of new Kir2.1 channel openers from propafenone analogues.

Background and purposes: Reduced inward rectifier potassium channel (Kir2.1) functioning is associated with heart failure and may cause Andersen-Tawil Syndrome, among others characterized by ventricular arrhythmias. Most heart failure or Andersen-Tawil Syndrome patients are treated with β-adrenoceptor antagonists (β-blockers) or sodium channel blockers; however, these do not specifically address the inward rectifier current (IK1) nor aim to improve resting membrane potential stability. Consequently, additional pharmacotherapy for heart failure and Andersen-Tawil Syndrome treatment would be highly desirable. Acute propafenone treatment at low concentrations enhances IK1 current, but it also exerts many off-target effects. Therefore, discovering and exploring new IK1-channel openers is necessary.

Experimental approach: Effects of propafenone and 10 additional propafenone analogues were analysed. Currents were measured by single-cell patch-clamp electrophysiology. Kir2.1 protein expression levels were determined by western blot analysis and action potential characteristics were further validated in human-induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMCs). Molecular docking was performed to obtain detailed information on drug-channel interactions.

Key results: Analogues GPV0019, GPV0057 and GPV0576 strongly increased the outward component of IK1 while not affecting the Kir2.1 channel expression levels. GPV0057 did not block IKr at concentrations below 0.5 μmol L-1 nor NaV1.5 current below 1 μmol L-1. Moreover, hiPSC-CMC action potential duration was also not affected by GPV0057 at 0.5 and 1 μmol L-1. Structure analysis indicates a mechanism by which GPV0057 might enhance Kir2.1 channel activation.

Conclusion and implications: GPV0057 has a strong efficiency towards increasing IK1, which makes it a good candidate to address IK1 deficiency-associated diseases.

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来源期刊
CiteScore
15.40
自引率
12.30%
发文量
270
审稿时长
2.0 months
期刊介绍: The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries. Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues. In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.
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