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Resumen: Small/intermediate conductance KCa channels (KCa2/3) are Ca2+/calmodulin regulated K+ channels that produce membrane hyperpolarization and shape neurologic, epithelial, cardiovascular, and immunologic functions. Moreover, they emerged as therapeutic targets to treat cardiovascular disease, chronic inflammation, and some cancers. Here, we aimed to generate a new pharmacophore for negative-gating modulation of KCa2/3 channels. We synthesized a series of mono- and dibenzoates and identified three dibenzoates [1,3-phenylenebis(methylene) bis(3-fluoro-4-hydroxybenzoate) (RA-2), 1,2-phenylenebis(methylene) bis(3-fluoro-4-hydroxybenzoate), and 1,4-phenylenebis(methylene) bis(3-fluoro-4-hydroxybenzoate)] with inhibitory efficacy as determined by patch clamp. Among them, RA-2 was the most drug-like and inhibited human KCa3.1 with an IC50 of 17 nM and all three human KCa2 subtypes with similar potencies. RA-2 at 100 nM right-shifted the KCa3.1 concentration-response curve for Ca2+ activation. The positive-gating modulator naphtho[1,2-d]thiazol-2-ylamine (SKA-31) reversed channel inhibition at nanomolar RA-2 concentrations. RA-2 had no considerable blocking effects on distantly related large-conductance KCa1.1, Kv1.2/1.3, Kv7.4, hERG, or inwardly rectifying K+ channels. In isometric myography on porcine coronary arteries, RA-2 inhibited bradykinin-induced endothelium-derived hyperpolarization (EDH)–type relaxation in U46619-precontracted rings. Blood pressure telemetry in mice showed that intraperitoneal application of RA-2 (=100 mg/kg) did not increase blood pressure or cause gross behavioral deficits. However, RA-2 decreased heart rate by ˜145 beats per minute, which was not seen in KCa3.1-/- mice. In conclusion, we identified the KCa2/3–negative-gating modulator, RA-2, as a new pharmacophore with nanomolar potency. RA-2 may be of use to generate structurally new types of negative-gating modulators that could help to define the physiologic and pathomechanistic roles of KCa2/3 in the vasculature, central nervous system, and during inflammation in vivo.
Idioma: Inglés
DOI: 10.1124/mol.114.095745
Año: 2015
Publicado en: Molecular Pharmacology 87, 2 (2015), 338-348
ISSN: 0026-895X
Factor impacto JCR: 3.931 (2015)
Categ. JCR: PHARMACOLOGY & PHARMACY rank: 45 / 255 = 0.176 (2015) - Q1 - T1
Factor impacto SCIMAGO: 2.037 - Pharmacology (Q1) - Molecular Medicine (Q1)

Financiación: info:eu-repo/grantAgreement/ES/DGA/GAE-102
Financiación: info:eu-repo/grantAgreement/ES/DGA/GIPASC-B105
Financiación: info:eu-repo/grantAgreement/EC/FP7/321721/EU/Identification and validation of cerebral KCa3.1/KCa2.3 potassium channels a drug tragets for the prevention and treatment of cerebral ischemia associated with diabetes and Alzheimers disease/BRAINIK
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/RD12-0042-0014
Tipo y forma: Artículo (Versión definitiva)
Área (Departamento): Área Fisiología (Dpto. Farmacología y Fisiolog.)
Área (Departamento): Área Química Orgánica (Dpto. Química Orgánica)

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