Biological Activity |
SKA-121 is a selective KCa3.1 activator. SKA-121 exhibits EC50s of 109 nM and 4.4 uM for KCa3.1 and KCa2.3, respectively. IC50 & Target: EC50: 109 nM (KCa3.1), 4.4 uM (KCa2.3)[1] In Vitro: SKA-121, a compound generated through an isosteric replacement approach. SKA-121 is a typical positive-gating modulator and shifts the calcium-concentration response curve of KCa3.1 to the left. SKA-121 displays 41-fold selectivity for KCa3.1 (EC50 109 nM+/-14 nM) over KCa2.3 (EC50 4.4 +/- 1.6 uM). SKA-121 is 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[1]. In Vivo: In blood pressure telemetry experiments, SKA-121 (100 mg/kg i.p.) significantly lowers mean arterial blood pressure in normotensive and hypertensive wild-type but not in KCa3.1-/- mice. SKA-121 can be used as a new KCa3.1 selective pharmacological tool compound despite its relatively short half-life in mice. A lower dose of 30 mg/kg of SKA-121 does not produce significant alterations in MAP. The vehicle, peanut oil/DMSO (9:1 v/v, for SKA-121), does not cause significant alterations in MAP or HR. SKA-121 has a short half-life (ca.20 minutes), and plasma decay is extremely rapid (21.3+/-2.4 uM at 5 minutes; 483+/-231 nM at 1 hour and 53+/-44 nM at 4 hours). Since SKA-121 is relatively well soluble (logP=1.79) and can potentially be added to drinking water in animal experiments, it orally is also administered, and find that it has an oral availability of roughly 25%[1]. |