Bernhard Nausch, Frederik Rode, Susanne Jørgensen, Antonio Nardi, Mads P G Korsgaard, Charlotte Hougaard, Adrian D Bonev, William D Brown, Tino Dyhring, Dorte Strøbæk, Søren-Peter Olesen, Palle Christophersen, Morten Grunnet, Mark T Nelson, Lars C B Rønn
Large-conductance Ca(2+)-activated K(+) channels (BK, KCa1.1, MaxiK) are important regulators of urinary bladder function and may be an attractive therapeutic target in bladder disorders. In this study, we established a high-throughput fluorometric imaging plate reader-based screening assay for BK channel activators and identified a small-molecule positive modulator, NS19504 (5-[(4-bromophenyl)methyl]-1,3-thiazol-2-amine), which activated the BK channel with an EC50 value of 11.0 ± 1.4 µM. Hit validation was performed using high-throughput electrophysiology (QPatch), and further characterization was achieved in manual whole-cell and inside-out patch-clamp studies in human embryonic kidney 293 cells expressing hBK channels: NS19504 caused distinct activation from a concentration of 0...
September 2014: Journal of Pharmacology and Experimental Therapeutics