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dc.contributor.authorOlivan-Viguera, Aida-
dc.contributor.authorValero Gracia, Marta Sofía-
dc.contributor.authorColeman, Nichole-
dc.contributor.authorBrown, Brandon M.-
dc.contributor.authorLaria Campaña, Celia-
dc.contributor.authorMurillo, Mª Divina-
dc.contributor.authorGálvez, José Antonio-
dc.contributor.authorDíaz-de-Villegas, María Dolores-
dc.contributor.authorWulff, Heike-
dc.contributor.authorBadorrey, Ramón-
dc.contributor.authorKöhler, Ralf-
dc.date.accessioned2021-03-10T11:20:46Z-
dc.date.available2021-03-10T11:20:46Z-
dc.date.issued2015-02-
dc.identifier.citationOliván-Viguera, A., Valero, M.S., Coleman, N., Brown, B.M., Laría, C., Divina Murillo, M., Gálvez, J.A., Díaz-De-Villegas, M.D., Wulff, H., Badorrey, R., Köhler, R., 2015. 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. Molecular Pharmacology 87, 338–348.. doi:10.1124/mol.114.095745es_ES
dc.identifier.issn1521-0111es_ES
dc.identifier.urihttps://repositorio.usj.es/handle/123456789/517-
dc.description.abstractSmall/intermediate conductance K-Ca channels (K(Ca)2/3) 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 K(Ca)2/3 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 K(Ca)3.1 with an IC50 of 17 nM and all three human K(Ca)2 subtypes with similar potencies. RA-2 at 100 nM right-shifted the K(Ca)3.1 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 K(Ca)1.1, 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 approximate to 145 beats per minute, which was not seen in K(Ca)3.1(-/-) mice. In conclusion, we identified the K(Ca)2/3-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 K(Ca)2/3 in the vasculature, central nervous system, and during inflammation in vivo.es_ES
dc.format.extent11 p.es_ES
dc.format.mimetypeapplication/pdfes_ES
dc.language.isoenges_ES
dc.publisherAMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICSes_ES
dc.relationA.O.-V. and R.K. were supported by the Deutsche Forschungsgemeinschaft [KO1899/11-1]; European Community [FP7-PEOPLE-CIG-321721]; the Danish Hjerteforening, Department of Industry and Innovation, Government of Aragon [GIPASC-B105]; REFBIO Pyrenees Biomedical Network; and the Fondo de Investigacion Sanitaria [Red HERACLES RD12/0042/0014]. J.A.G., M.D.D., and R.B. were supported from the Government of Aragon [GA E-102]. B.M.B. was supported by a NIGMS-funded Pharmacology Training Program [T32GM099608]. N.C. was supported by a NIHLB-funded Training Program in Basic and Translational Cardiovascular Science [T32HL086350]. H.W. was supported by the National Institute of Neurologic Disorders and Stroke (NINDS) [R21NS072585].es_ES
dc.relation.requiresAdobe PDFes_ES
dc.rightsAtribución 4.0 Internacional*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectCA2+-ACTIVATED K+ CHANNELes_ES
dc.subjectACTIVATED POTASSIUM CHANNELSes_ES
dc.subjectSMALL-CONDUCTANCEes_ES
dc.subjectK(CA)3.1es_ES
dc.subjectATRIALes_ES
dc.subjectSKA-31es_ES
dc.subjectSK3es_ES
dc.subjectEXPRESSIONes_ES
dc.subjectPHARMACOLOGYes_ES
dc.subjectCONTRIBUTESes_ES
dc.titleA Novel Pan-Negative-Gating Modulator of K(Ca)2/3 Channels, Fluoro-Di-Benzoate, RA-2, Inhibits Endothelium-Derived Hyperpolarization-Type Relaxation in Coronary Artery and Produces Bradycardia In Vivoes_ES
dc.typeinfo:eu-repo/semantics/articlees_ES
dc.relation.publisherversionhttps://molpharm.aspetjournals.org/content/87/2/338.abstractes_ES
dc.identifier.publicationfirstpage338es_ES
dc.identifier.publicationlastpage348es_ES
dc.identifier.doi10.1124/mol.114.095745es_ES
dc.rights.accessrightsinfo:eu-repo/semantics/openAccesses_ES
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