ArticleMolecular pharmacology2014
New positive Ca2+-activated K+ channel gating modulators with selectivity for KCa3.1.
Article in Molecular pharmacology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed.
- Structural basis for the subtype-selective activation of KStructure (London, England : 1993) · 2026Article
- Mutation-Induced Pocket Deactivation: How Ser353/Pro245 Alters KArchiv der Pharmazie · 2026Article
- KCa3.1 channels regulate the tumor infiltration of functionally competent NK cells in head and neck cancer.Scientific reports · 2025Article
- The novel quinoline derivative SKA-346 as a KRSC advances · 2024Article
- Alternative Targets for Modulators of Mitochondrial Potassium Channels.Molecules (Basel, Switzerland) · 2022Review
- Ion Channels in Glioma Malignancy.Reviews of physiology, biochemistry and pharmacology · 2021Review
- Calcium-Activated KHandbook of experimental pharmacology · 2021Article
- Molecular Choreography and Structure of CaMembranes · 2020Review
- Article
- KCells · 2020Review
- Pharmacology of Small- and Intermediate-Conductance Calcium-Activated Potassium Channels.Annual review of pharmacology and toxicology · 2020Review
- A Compartmentalized Reduction in Membrane-Proximal Calmodulin Reduces the Immune Surveillance Capabilities of CD8Frontiers in pharmacology · 2020Article
- Cancer-Associated Intermediate Conductance CaCancers · 2019Review
- The Trials and Tribulations of Structure Assisted Design of KFrontiers in pharmacology · 2019Article
- Effect of high-fat diet-induced obesity on the small-conductance CaInternational urology and nephrology · 2019Article
- A defect in KCa3.1 channel activity limits the ability of CD8Science signaling · 2018Article
- Comparing Effects of Transforming Growth Factor β1 on Microglia From Rat and Mouse: Transcriptional Profiles and Potassium Channels.Frontiers in cellular neuroscience · 2018Article
- KCa3.1 Channel Modulators as Potential Therapeutic Compounds for Glioblastoma.Current neuropharmacology · 2018Article
- Pharmacologic targeting of endothelial CaChannels (Austin, Tex.) · 2018Review
- Structural Determinants for the Selectivity of the Positive KCa3.1 Gating Modulator 5-Methylnaphtho[2,1-Molecular pharmacology · 2017Article
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8 authors.
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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.
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