000065623 001__ 65623
000065623 005__ 20180228102248.0
000065623 0247_ $$2doi$$a10.1124/mol.114.095745
000065623 0248_ $$2sideral$$a89292
000065623 037__ $$aART-2015-89292
000065623 041__ $$aeng
000065623 100__ $$0(orcid)0000-0001-5348-924X$$aOliván-Viguera, Aida
000065623 245__ $$aA novel pan-negative-gating modulator of KCa2/3 channels, fluoro-di-benzoate, RA-2, inhibits Endothelium-derived hyperpolarization–type relaxation in coronary artery and produces bradycardia in vivo
000065623 260__ $$c2015
000065623 5060_ $$aAccess copy available to the general public$$fUnrestricted
000065623 5203_ $$aSmall/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.
000065623 536__ $$9info:eu-repo/grantAgreement/ES/DGA/GAE-102$$9info:eu-repo/grantAgreement/ES/DGA/GIPASC-B105$$9info:eu-repo/grantAgreement/EUR/FP7/PEOPLE-321721$$9info:eu-repo/grantAgreement/ES/ISCIII/RD12-0042-0014
000065623 540__ $$9info:eu-repo/semantics/openAccess$$aAll rights reserved$$uhttp://www.europeana.eu/rights/rr-f/
000065623 590__ $$a3.931$$b2015
000065623 591__ $$aPHARMACOLOGY & PHARMACY$$b45 / 255 = 0.176$$c2015$$dQ1$$eT1
000065623 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000065623 700__ $$0(orcid)0000-0002-2231-7565$$aValero, Marta Sofía
000065623 700__ $$aColeman, Nicole
000065623 700__ $$aBrown, Brandon M.
000065623 700__ $$aLaría, Celia
000065623 700__ $$0(orcid)0000-0002-3917-4740$$aMurillo, María Divina
000065623 700__ $$0(orcid)0000-0002-4972-7476$$aGálvez, José A.$$uUniversidad de Zaragoza
000065623 700__ $$0(orcid)0000-0001-9033-8459$$aDíaz-de-Villegas, María D.
000065623 700__ $$aWulff, Heike
000065623 700__ $$0(orcid)0000-0002-5554-3040$$aBadorrey, Ramón$$uUniversidad de Zaragoza
000065623 700__ $$aKöhler, Ralf
000065623 7102_ $$12013$$2765$$aUniversidad de Zaragoza$$bDepartamento de Química Orgánica$$cQuímica Orgánica
000065623 773__ $$g87, 2 (2015), 338-348$$pMol. pharmacol.$$tMOLECULAR PHARMACOLOGY$$x0026-895X
000065623 8564_ $$s807358$$uhttp://zaguan.unizar.es/record/65623/files/texto_completo.pdf$$yVersión publicada
000065623 8564_ $$s141563$$uhttp://zaguan.unizar.es/record/65623/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000065623 909CO $$ooai:zaguan.unizar.es:65623$$particulos$$pdriver
000065623 951__ $$a2018-02-28-10:17:24
000065623 980__ $$aARTICLE