Abstract
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 in vitro. The potency of BBP was measured using automatic patch clamp on all three SK channel subtypes, resulting in similar IC50 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, Kir2.1, Kir3.1+Kir3.4, Kv1.5, Kv4.3/KCHIP2 and Kv7.1/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.
Highlights
IntroductionSmall conductance calcium-activated potassium (SK) channels are ion channels that open when the intracellular calcium concentration is increased, allowing the passage of potassium ions through cell membrane
Small conductance calcium-activated potassium (SK) channels are ion channels that open when the intracellular calcium concentration is increased, allowing the passage of potassium ions through cell membrane. These submicromolar changes in the intracellular calcium concentration are sensed by the protein calmodulin, which is covalently attached to the C-terminus of the channel (Adelman, 2016)
Since the discovery of apamin, a neurotoxin extracted from bee venom and the first specific SK inhibitor described (Habermann, 1984), the lists of both SK channel activators and inhibitors have grown (Weatherall et al, 2010; Christophersen and Wulff, 2015), including most recently the negative allosteric modulator AP14145
Summary
Small conductance calcium-activated potassium (SK) channels are ion channels that open when the intracellular calcium concentration is increased, allowing the passage of potassium ions through cell membrane. BBP Selectively Blocks SK Channels (Diness et al, 2017; Simó-Vicens et al, 2017a) and the natural flavone acacetin (Chen et al, 2017). Some of these compounds may be difficult to access and/or use for a number of reasons such as low potency, incomplete pharmacological characterization or commercial unavailability
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