AUTHOR=Simó-Vicens Rafel , Bomholtz Sofia H. , Sørensen Ulrik S. , Bentzen Bo H. 

TITLE=2,6-Bis(2-Benzimidazolyl)Pyridine (BBP) Is a Potent and Selective Inhibitor of Small Conductance Calcium-Activated Potassium (SK) Channels

JOURNAL=Frontiers in Pharmacology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2018.01409

DOI=10.3389/fphar.2018.01409

ISSN=1663-9812

ABSTRACT=<p>A variety of polycyclic pyridines have been proposed as inhibitors of the small conductance calcium-activated potassium (SK) channel. To this group belongs 2,6-bis(2-benzimidazolyl)pyridine (BBP), a commercially and readily available small organic compound which has earlier been described in a broad range of chemical and biological uses. Here, we show how BBP can also be used as a potent and specific SK channel blocker <italic>in vitro</italic>. The potency of BBP was measured using automatic patch clamp on all three SK channel subtypes, resulting in similar IC<sub>50</sub> of 0.4 μM. We also assessed the selectivity of BBP on a panel of calcium-activated and voltage-activated potassium channels using two-electrode voltage clamp, automatic and manual patch clamp. BBP did not have any effect on IK, K<sub>ir</sub>2.1, K<sub>ir</sub>3.1+K<sub>ir</sub>3.4, K<sub>v</sub>1.5, K<sub>v</sub>4.3/K<sub>CHIP</sub>2 and K<sub>v</sub>7.1/KCNE1 currents and was 4.8-fold and 46-fold more potent on all SK channel subtypes vs. BK and hERG channels, respectively. Moreover, we were able to identify H491 as a critical amino acid for the pharmacological effect of BBP on the SK channel. From a medicinal chemistry perspective, BBP could be used as a starting point for the design of new and improved SK inhibitors.</p>