Development of new K2.1 channel openers from propafenone analogues.

BACKGROUND AND PURPOSES

Reduced inward rectifier potassium channel (K2.1) 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) 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 current, but it also exerts many off-target effects. Therefore, discovering and exploring new I-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. K2.1 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 while not affecting the K2.1 channel expression levels. GPV0057 did not block I at concentrations below 0.5 μmol L nor Na1.5 current below 1 μmol L. Moreover, hiPSC-CMC action potential duration was also not affected by GPV0057 at 0.5 and 1 μmol L. Structure analysis indicates a mechanism by which GPV0057 might enhance K2.1 channel activation.

CONCLUSION AND IMPLICATIONS

GPV0057 has a strong efficiency towards increasing I, which makes it a good candidate to address I deficiency-associated diseases.

© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.