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Mol Pharmacol. 2014 Sep;86(3):342-57. doi: 10.1124/mol.114.093286. Epub 2014 Jun 23.

New positive Ca2+-activated K+ channel gating modulators with selectivity for KCa3.1.

Author information

1
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.).
2
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.

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.

PMID:
24958817
PMCID:
PMC4152908
DOI:
10.1124/mol.114.093286
[Indexed for MEDLINE]
Free PMC Article

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