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

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.contributor.authorVarela, Diego
dc.contributor.authorWiedmann, Felix
dc.contributor.authorMárquez Montesinos, José C. E
dc.contributor.authorMazola, Yuliet
dc.contributor.authorVenturini, Whitney
dc.contributor.authorZúñiga, Rafael
dc.contributor.authorZúñiga, Leandro
dc.contributor.authorSchmidt, Constanze
dc.contributor.authorRodriguez, Blanca
dc.contributor.authorRavens, Ursula
dc.contributor.authorDecher, Niels
dc.contributor.authorGutiérrez, Margarita
dc.contributor.authorGonzález, Wendy
dc.date.accessioned2025-07-01T14:10:14Z
dc.date.available2025-07-01T14:10:14Z
dc.date.issued2025
dc.identifier.urihttp://repositorio.ucm.cl/handle/ucm/6152
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.es_CL
dc.language.isoenes_CL
dc.rightsAtribución-NoComercial-SinDerivadas 3.0 Chile*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/cl/*
dc.sourceJournal of Biological Chemistry, 301(4), 108387es_CL
dc.subjectAtrial fibrillationes_CL
dc.subjectIon channelses_CL
dc.subjectK2P channelses_CL
dc.subjectKV1.5es_CL
dc.subjectNaV1.5es_CL
dc.subjectPolypharmacologyes_CL
dc.subjectMulti-target inhibitorses_CL
dc.titleRational design, synthesis, and evaluation of novel polypharmacological compounds targeting NaV1.5, KV1.5, and K2P channels for atrial fibrillationes_CL
dc.typeArticlees_CL
dc.ucm.facultadFacultad de Medicinaes_CL
dc.ucm.indexacionScopuses_CL
dc.ucm.indexacionIsies_CL
dc.ucm.urijbc.org/article/S0021-9258(25)00236-4/fulltextes_CL
dc.ucm.doidoi.org/10.1016/j.jbc.2025.108387es_CL


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Atribución-NoComercial-SinDerivadas 3.0 Chile
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