Work

Development of new K ir 2.1 channel openers from propafenone analogues

Year: 2024

Type: article

Abstract: Background and Purposes Reduced inward rectifier potassium channel (K ir 2.1) 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 (I K1 ) 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 I K1 current, but it also exerts many off‐target effects. Therefore, discovering and exploring new I K1 ‐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. K ir 2.1 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 I K1 while not affecting the K ir 2.1 channel expression levels. GPV0057 did not block I Kr at concentrations below 0.5 μmol L −1 nor Na V 1.5 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 K ir 2.1 channel activation. Conclusion and Implications GPV0057 has a strong efficiency towards increasing I K1 , which makes it a good candidate to address I K1 deficiency‐associated diseases.

Source: British Journal of Pharmacology

DOI: 10.1111/bph.17377