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A novel pan-negative-gating modulator of KCa2/3 channels, fluoro-di-benzoate, RA-2, inhibits endothelium-derived hyperpolarization-type relaxation in coronary artery and produces bradycardia in vivo

AuthorsOliván-Viguera, Aida; Gálvez, José A. ; Díaz de Villegas, María D. ; Badorrey, Ramón ; Köhler, Ralf
Potassium channels
Antiarrhythmic drugs
Issue Date2015
PublisherAmerican Society for Pharmacology and Experimental Therapeutics
CitationMolecular Pharmacology 87(2): 338-348 (2015)
AbstractKCa2/3 channels are Ca2+/calmodulin-regulated K+ channels that produce membrane hyperpolarization and shape neurological, epithelial, cardiovascular, and immunological 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 di-benzoates and identified three di-benzoates (RA-2, RA-3, and RA-4) with inhibitory efficacy as determined by patch-clamp. Among them, RA-2 (1,3-phenylenebis(methylene)bis(3-fluoro-4-hydroxybenzoate) 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 SKA-31 reversed channel inhibition at nanomolar RA-2 concentrations. RA-2 had no considerable blocking effects on distantly related KCa1.1, Kv1.2/1.3, Kv7.4, hERG, or KIR channels. In isometric myography on porcine coronary arteries, RA-2 inhibited bradykinin-induced endothelium-derived hyperpolarization (EDH)-type relaxation in U46610-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 bpm, 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 physiological and pathomechanistic roles of KCa2/3 in the vasculature, CNS, and during inflammation in vivo.
Descriptionet al.
Identifiersdoi: 10.1124/mol.114.095745
issn: 0026-895X
e-issn: 1521-0111
Appears in Collections:(ISQCH) Artículos
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