SKA-121

SKA-121 is a positive-gating modulator of intermediate-conductance calcium-activated potassium channels (IKCa1/K_Ca3.1) with an EC₅₀ value of 109 nM using whole-cell patch-clamp electrophysiology with calcium in the internal solution.¹ It is selective for K_Ca3.1 over K_Ca2.1, K_Ca2.2 and K_Ca2.3 (EC₅₀s = 8,700, 6,800, and 4,400 nM, respectively).² It is also selective over K_Ca1.1 as well as voltage-gated potassium and sodium channels. SKA-121 (1 µM) potentiates calcium-evoked K_Ca currents by approximately 7-fold using whole-cell patch-clamp electrophysiology, an effect that can be blocked by the K_Ca3.1 inhibitor TRAM-34 (Item No. 23385).¹ It also potentiates calcium-evoked and basal K_Ca currents. In large porcine coronary arteries ex vivo, SKA-121 potentiates bradykinin-induced endothelium-dependent relaxation (EC₅₀ = 7.9 nM). It also lowers mean arterial blood pressure (MAP) by approximately 20 and 25 mm Hg in normo- and hypertensive mice when used at a dose of 100 mg/kg but has no effect on MAP in K_Ca3.1 knockout mice.²

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1. Oliván-Viguera, A., Valero, M.S., Pinilla, E., et al. Vascular reactivity profile of novel KCa3.1-selective positive-gating modulators in the coronary vascular bed. Basic Clin. Pharmacol. Toxicol. 119(2), 184-192 (2016).

2. Coleman, N., Brown, B.M., Oliván-Viguera, A., et al. New positive Ca²⁺-activated K⁺ channel gating modulators with selectivity for KCa3.1. Mol. Pharmacol. 86(3), 342-357 (2014).