title: New positive Ca2+-activated K+ channel gating modulators with selectivity for KCa3.1.
abstract: Small-conductance (KCa2) and intermediate-conductance (KCa3.1) calcium-activated K(+) channels are voltage-independent and share a common calcium/calmodulin-mediated gating mechanism. Existing positive gating modulators like EBIO, NS309, or SKA-31 activate both KCa2 and KCa3.1 channels with similar potency or, as in the case of CyPPA and NS13001, selectively activate KCa2.2 and KCa2.3 channels. We performed a structure-activity relationship (SAR) study with the aim of optimizing the benzothiazole pharmacophore of SKA-31 toward KCa3.1 selectivity. We identified SKA-111 (5-methylnaphtho[1,2-d]thiazol-2-amine), which displays 123-fold selectivity for KCa3.1 (EC50 111 ± 27 nM) over KCa2.3 (EC50 13.7 ± 6.9 μM), and SKA-121 (5-methylnaphtho[2,1-d]oxazol-2-amine), which displays 41-fold selectivity for KCa3.1 (EC50 109 nM ± 14 nM) over KCa2.3 (EC50 4.4 ± 1.6 μM). Both compounds are 200- to 400-fold selective over representative KV (KV1.3, KV2.1, KV3.1, and KV11.1), NaV (NaV1.2, NaV1.4, NaV1.5, and NaV1.7), as well as CaV1.2 channels. SKA-121 is a typical positive-gating modulator and shifts the calcium-concentration response curve of KCa3.1 to the left. In blood pressure telemetry experiments, SKA-121 (100 mg/kg i.p.) significantly lowered mean arterial blood pressure in normotensive and hypertensive wild-type but not in KCa3.1(-/-) mice. SKA-111, which was found in pharmacokinetic experiments to have a much longer half-life and to be much more brain penetrant than SKA-121, not only lowered blood pressure but also drastically reduced heart rate, presumably through cardiac and neuronal KCa2 activation when dosed at 100 mg/kg. In conclusion, with SKA-121, we generated a KCa3.1-specific positive gating modulator suitable for further exploring the therapeutical potential of KCa3.1 activation.
authors: Department of Pharmacology (N.C., B.M.B., V.S., H.W.), School of Medicine, and Department of Chemistry (M.M.O.), University of California, Davis, California; Aragon Institute of Health Sciences, Instituto de Investigación Sanitaria, Fundación Agencia Aragonesa para la Investigación y el Desarrollo, Zaragoza, Spain (A.O.-V., R.K.); and Grupo de Investigación del Medio Ambiente del Centro de Estudios Superiores, Faculty of Health Sciences, Universidad San Jorge, Villanueva de Gállego, Spain (M.S.V.).
authors: Nichole
authors: N
authors: Coleman
authors: Department of Pharmacology (N.C., B.M.B., V.S., H.W.), School of Medicine, and Department of Chemistry (M.M.O.), University of California, Davis, California; Aragon Institute of Health Sciences, Instituto de Investigación Sanitaria, Fundación Agencia Aragonesa para la Investigación y el Desarrollo, Zaragoza, Spain (A.O.-V., R.K.); and Grupo de Investigación del Medio Ambiente del Centro de Estudios Superiores, Faculty of Health Sciences, Universidad San Jorge, Villanueva de Gállego, Spain (M.S.V.).
authors: Brandon M
authors: BM
authors: Brown
authors: Department of Pharmacology (N.C., B.M.B., V.S., H.W.), School of Medicine, and Department of Chemistry (M.M.O.), University of California, Davis, California; Aragon Institute of Health Sciences, Instituto de Investigación Sanitaria, Fundación Agencia Aragonesa para la Investigación y el Desarrollo, Zaragoza, Spain (A.O.-V., R.K.); and Grupo de Investigación del Medio Ambiente del Centro de Estudios Superiores, Faculty of Health Sciences, Universidad San Jorge, Villanueva de Gállego, Spain (M.S.V.).
authors: Aida
authors: A
authors: Oliván-Viguera
authors: Department of Pharmacology (N.C., B.M.B., V.S., H.W.), School of Medicine, and Department of Chemistry (M.M.O.), University of California, Davis, California; Aragon Institute of Health Sciences, Instituto de Investigación Sanitaria, Fundación Agencia Aragonesa para la Investigación y el Desarrollo, Zaragoza, Spain (A.O.-V., R.K.); and Grupo de Investigación del Medio Ambiente del Centro de Estudios Superiores, Faculty of Health Sciences, Universidad San Jorge, Villanueva de Gállego, Spain (M.S.V.).
authors: Vikrant
authors: V
authors: Singh
authors: Department of Pharmacology (N.C., B.M.B., V.S., H.W.), School of Medicine, and Department of Chemistry (M.M.O.), University of California, Davis, California; Aragon Institute of Health Sciences, Instituto de Investigación Sanitaria, Fundación Agencia Aragonesa para la Investigación y el Desarrollo, Zaragoza, Spain (A.O.-V., R.K.); and Grupo de Investigación del Medio Ambiente del Centro de Estudios Superiores, Faculty of Health Sciences, Universidad San Jorge, Villanueva de Gállego, Spain (M.S.V.).
authors: Marilyn M
authors: MM
authors: Olmstead
authors: Department of Pharmacology (N.C., B.M.B., V.S., H.W.), School of Medicine, and Department of Chemistry (M.M.O.), University of California, Davis, California; Aragon Institute of Health Sciences, Instituto de Investigación Sanitaria, Fundación Agencia Aragonesa para la Investigación y el Desarrollo, Zaragoza, Spain (A.O.-V., R.K.); and Grupo de Investigación del Medio Ambiente del Centro de Estudios Superiores, Faculty of Health Sciences, Universidad San Jorge, Villanueva de Gállego, Spain (M.S.V.).
authors: Marta Sofia
authors: MS
authors: Valero
authors: Department of Pharmacology (N.C., B.M.B., V.S., H.W.), School of Medicine, and Department of Chemistry (M.M.O.), University of California, Davis, California; Aragon Institute of Health Sciences, Instituto de Investigación Sanitaria, Fundación Agencia Aragonesa para la Investigación y el Desarrollo, Zaragoza, Spain (A.O.-V., R.K.); and Grupo de Investigación del Medio Ambiente del Centro de Estudios Superiores, Faculty of Health Sciences, Universidad San Jorge, Villanueva de Gállego, Spain (M.S.V.).
authors: Ralf
authors: R
authors: Köhler
authors: Department of Pharmacology (N.C., B.M.B., V.S., H.W.), School of Medicine, and Department of Chemistry (M.M.O.), University of California, Davis, California; Aragon Institute of Health Sciences, Instituto de Investigación Sanitaria, Fundación Agencia Aragonesa para la Investigación y el Desarrollo, Zaragoza, Spain (A.O.-V., R.K.); and Grupo de Investigación del Medio Ambiente del Centro de Estudios Superiores, Faculty of Health Sciences, Universidad San Jorge, Villanueva de Gállego, Spain (M.S.V.) hwulff@ucdavis.edu.
authors: Heike
authors: H
authors: Wulff
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000494:pharmacology; D019556:COS Cells; D002522:Chlorocebus aethiops; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D018360:Crystallography, X-Ray; D057809:HEK293 Cells; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000235:genetics / Q000378:metabolism*; D015640:Ion Channel Gating; D007537:Isometric Contraction; D008297:Male; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D010080:Oxazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013552:Swine; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: C000591919:5-methylnaphtho(2,1-d)oxazol-2-amine; D052160:Benzothiazoles; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; D010080:Oxazoles; D014665:Vasodilator Agents; C535212:naphtho(1,2-d)thiazol-2-ylamine; D001920:Bradykinin