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Molecular Pharmacology

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Research ArticleArticle

New Positive Ca2+-Activated K+ Channel Gating Modulators with Selectivity for KCa3.1

Nichole Coleman, Brandon M. Brown, Aida Oliván-Viguera, Vikrant Singh, Marilyn M. Olmstead, Marta Sofia Valero, Ralf Köhler and Heike Wulff
Molecular Pharmacology September 2014, 86 (3) 342-357; DOI: https://doi.org/10.1124/mol.114.093286
Nichole Coleman
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.)
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Brandon M. Brown
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.)
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Aida Oliván-Viguera
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.)
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Vikrant Singh
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.)
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Marilyn M. Olmstead
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.)
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Marta Sofia Valero
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.)
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Ralf Köhler
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.)
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Heike Wulff
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.)
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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.

Footnotes

    • Received April 14, 2014.
    • Accepted June 23, 2014.
  • N.C. and B.M.B. contributed equally to this work. R.K. and H.W. are co-senior authors.

  • This work was supported by the CounterACT Program, National Institutes of Health (NIH) Office of the Director [Grant U54NS079202] and National Institute of Neurological Disorders and Stroke [R21NS072585], the Deutsche Forschungsgemeinschaft [Grant KO1899/11-1], the Danish Hjerteforening, and the Fondo de Investigación Sanitaria [Red HERACLES RD12/0042/0014]. N.C. was supported by an NIH National Heart, Lung and Blood Institute T32 Training Program in Basic and Translational Cardiovascular Science [Grant T32HL086350]. B.M.B. was supported by an NIH National Institute of General Medical Sciences–funded Pharmacology Training Program [Grant T32GM099608].

  • The work forms part of the Ph.D. thesis of Nichole Coleman in fulfillment of the degree requirements of the University of California, Davis.

  • dx.doi.org/10.1124/mol.114.093286.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 86 (3)
Molecular Pharmacology
Vol. 86, Issue 3
1 Sep 2014
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Research ArticleArticle

Positive Gating Modulation of KCa3.1

Nichole Coleman, Brandon M. Brown, Aida Oliván-Viguera, Vikrant Singh, Marilyn M. Olmstead, Marta Sofia Valero, Ralf Köhler and Heike Wulff
Molecular Pharmacology September 1, 2014, 86 (3) 342-357; DOI: https://doi.org/10.1124/mol.114.093286

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Research ArticleArticle

Positive Gating Modulation of KCa3.1

Nichole Coleman, Brandon M. Brown, Aida Oliván-Viguera, Vikrant Singh, Marilyn M. Olmstead, Marta Sofia Valero, Ralf Köhler and Heike Wulff
Molecular Pharmacology September 1, 2014, 86 (3) 342-357; DOI: https://doi.org/10.1124/mol.114.093286
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