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
{"title":"从普罗帕酮类似物中开发新的 Kir2.1 通道开启剂。","authors":"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","doi":"10.1111/bph.17377","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and purposes: </strong>Reduced inward rectifier potassium channel (K<sub>ir</sub>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<sub>K1</sub>) 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<sub>K1</sub> current, but it also exerts many off-target effects. Therefore, discovering and exploring new I<sub>K1</sub>-channel openers is necessary.</p><p><strong>Experimental approach: </strong>Effects of propafenone and 10 additional propafenone analogues were analysed. Currents were measured by single-cell patch-clamp electrophysiology. K<sub>ir</sub>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.</p><p><strong>Key results: </strong>Analogues GPV0019, GPV0057 and GPV0576 strongly increased the outward component of I<sub>K1</sub> while not affecting the K<sub>ir</sub>2.1 channel expression levels. GPV0057 did not block I<sub>Kr</sub> at concentrations below 0.5 μmol L<sup>-1</sup> nor Na<sub>V</sub>1.5 current below 1 μmol L<sup>-1</sup>. Moreover, hiPSC-CMC action potential duration was also not affected by GPV0057 at 0.5 and 1 μmol L<sup>-1</sup>. Structure analysis indicates a mechanism by which GPV0057 might enhance K<sub>ir</sub>2.1 channel activation.</p><p><strong>Conclusion and implications: </strong>GPV0057 has a strong efficiency towards increasing I<sub>K1</sub>, which makes it a good candidate to address I<sub>K1</sub> deficiency-associated diseases.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8000,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Development of new K<sub>ir</sub>2.1 channel openers from propafenone analogues.\",\"authors\":\"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\",\"doi\":\"10.1111/bph.17377\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background and purposes: </strong>Reduced inward rectifier potassium channel (K<sub>ir</sub>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<sub>K1</sub>) 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<sub>K1</sub> current, but it also exerts many off-target effects. Therefore, discovering and exploring new I<sub>K1</sub>-channel openers is necessary.</p><p><strong>Experimental approach: </strong>Effects of propafenone and 10 additional propafenone analogues were analysed. Currents were measured by single-cell patch-clamp electrophysiology. K<sub>ir</sub>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.</p><p><strong>Key results: </strong>Analogues GPV0019, GPV0057 and GPV0576 strongly increased the outward component of I<sub>K1</sub> while not affecting the K<sub>ir</sub>2.1 channel expression levels. GPV0057 did not block I<sub>Kr</sub> at concentrations below 0.5 μmol L<sup>-1</sup> nor Na<sub>V</sub>1.5 current below 1 μmol L<sup>-1</sup>. Moreover, hiPSC-CMC action potential duration was also not affected by GPV0057 at 0.5 and 1 μmol L<sup>-1</sup>. Structure analysis indicates a mechanism by which GPV0057 might enhance K<sub>ir</sub>2.1 channel activation.</p><p><strong>Conclusion and implications: </strong>GPV0057 has a strong efficiency towards increasing I<sub>K1</sub>, which makes it a good candidate to address I<sub>K1</sub> deficiency-associated diseases.</p>\",\"PeriodicalId\":9262,\"journal\":{\"name\":\"British Journal of Pharmacology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":6.8000,\"publicationDate\":\"2024-10-17\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"British Journal of Pharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1111/bph.17377\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"British Journal of Pharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1111/bph.17377","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
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.
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.