Development of new K ir 2.1 channel openers from propafenone analogues.

Autor: Li E; Department of Medical Physiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands., Boujeddaine N; Department of Medical Physiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands., Houtman MJC; Department of Medical Physiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands., Maas RGC; Department of Cardiology, Laboratory of Experimental Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.; Circulatory Health Research Center, Regenerative Medicine Center Utrecht, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands., Sluijter JPG; Department of Cardiology, Laboratory of Experimental Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.; Circulatory Health Research Center, Regenerative Medicine Center Utrecht, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands., Ecker GF; Department of Pharmaceutical Sciences, University of Vienna, Vienna, Austria., Stary-Weinzinger A; Department of Pharmaceutical Sciences, University of Vienna, Vienna, Austria., van Ham WB; Department of Medical Physiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands., van der Heyden MAG; Department of Medical Physiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2024 Oct 17. Date of Electronic Publication: 2024 Oct 17.
DOI: 10.1111/bph.17377
Abstrakt: 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.
(© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Databáze: MEDLINE
Externí odkaz: