Rational design, synthesis, and evaluation of novel polypharmacological compounds targeting NaV1.5, KV1.5, and K2P channels for atrial fibrillation

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dc.contributor.authorCamargo-Ayala, Lorena
dc.contributor.authorBedoya, Mauricio
dc.contributor.authorDasí, Albert
dc.contributor.authorPrüser, Merten
dc.contributor.authorSchütte, Sven
dc.contributor.authorPrent-Peñaloza, Luis
dc.contributor.authorAdasme-Carreño, Francisco
dc.contributor.authorKiper, Aytug K.
dc.contributor.authorRinné, Susanne
dc.contributor.authorCamargo-Ayala, Paola Andrea
dc.contributor.authorPeña-Martínez, Paula A.
dc.contributor.authorBueno-Orovio, Alfonso
dc.date.accessioned2025-05-19T13:31:06Z
dc.date.available2025-05-19T13:31:06Z
dc.date.issued2025-04
dc.descriptionIndexación (Scopus)
dc.description.abstractAtrial fibrillation (AF) involves electrical remodeling of the atria, with ion channels such as NaV1.5, KV1.5, and TASK-1 playing crucial roles. This study investigates acetamide-based compounds designed as multi-target inhibitors of these ion channels to address AF. Compound 6f emerged as the most potent in the series, demonstrating a strong inhibition of TASK-1 (IC50 ∼ 0.3 μM), a moderate inhibition of NaV1.5 (IC50 ∼ 21.2 μM) and a subtle inhibition of KV1.5 (IC50 ∼ 81.5 μM), alongside unexpected activation of TASK-4 (∼ 40% at 100 μM). Functional assays on human atrial cardiomyocytes from sinus rhythm (SR) and patients with AF revealed that 6f reduced action potential amplitude in SR (indicating NaV1.5 block), while in AF it increased action potential duration (APD), reflecting high affinity for TASK-1. Additionally, 6f caused hyperpolarization of the resting membrane potential in AF cardiomyocytes, consistent with the observed TASK-4 activation. Mathematical modeling further validated its efficacy in reducing AF burden. Pharmacokinetic analyses suggest favorable absorption and low toxicity. These findings identify 6f as a promising multi-target therapeutic candidate for AF management.
dc.description.urihttps://www.sciencedirect.com/science/article/pii/S0021925825002364?pes=vor&utm_source=scopus&getft_integrator=scopus
dc.identifier.citationJournal of Biological Chemistry Volume 301, Issue 4 April 2025 Article number 108387
dc.identifier.doi10.1016/j.jbc.2025.108387
dc.identifier.issn0021-9258
dc.identifier.urihttps://repositorio.unab.cl/handle/ria/64735
dc.language.isoen
dc.publisherAmerican Society for Biochemistry and Molecular Biology Inc.
dc.subjectatrial fibrillation
dc.subjection channels
dc.subjectK2P channels
dc.subjectKV1.5
dc.subjectmulti-target inhibitors
dc.subjectNaV1.5
dc.subjectPolypharmacology
dc.titleRational design, synthesis, and evaluation of novel polypharmacological compounds targeting NaV1.5, KV1.5, and K2P channels for atrial fibrillation
dc.typeArtículo
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