2. Academic Validation
  3. Development of new Kir2.1 channel openers from propafenone analogues

Development of new Kir2.1 channel openers from propafenone analogues

  • Br J Pharmacol. 2025 Feb;182(3):633-650. doi: 10.1111/bph.17377.
Encan Li 1,  Najla Boujeddaine 1,  Marien J C Houtman 1,  Renee G C Maas 2 3,  Joost P G Sluijter 2 3,  Gerhard F Ecker 4,  Anna Stary-Weinzinger 4,  Willem B van Ham 1,  Marcel A G van der Heyden 1
Affiliations

Affiliations

  • 1 Department of Medical Physiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.
  • 2 Department of Cardiology, Laboratory of Experimental Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.
  • 3 Circulatory Health Research Center, Regenerative Medicine Center Utrecht, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands.
  • 4 Department of Pharmaceutical Sciences, University of Vienna, Vienna, Austria.
PMID: 39419581 DOI: 10.1111/bph.17377
Abstract

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.

Keywords

Kir2.1 channel; cardiac pharmacology; drug discovery/target validation; hiPSC‐CMCs; ion channels; off‐target effects; propafenone analogues.

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