Simó-Vicens Rafel, Bomholtz Sofia H, Sørensen Ulrik S, Bentzen Bo H
Cardiovascular Pharmacology, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Acesion Pharma, Copenhagen, Denmark.
Front Pharmacol. 2018 Dec 3;9:1409. doi: 10.3389/fphar.2018.01409. eCollection 2018.
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 . The potency of BBP was measured using automatic patch clamp on all three SK channel subtypes, resulting in similar IC 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, K2.1, K3.1+K3.4, K1.5, K4.3/K2 and K7.1/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.
多种多环吡啶已被提议作为小电导钙激活钾（SK）通道的抑制剂。2,6-双（2-苯并咪唑基）吡啶（BBP）属于这一类，它是一种商业上容易获得的小有机化合物，此前已在广泛的化学和生物学用途中有所描述。在此，我们展示了BBP如何也能用作一种强效且特异性的SK通道阻滞剂。使用自动膜片钳对所有三种SK通道亚型测量了BBP的效力，得到的半数抑制浓度（IC）相似，均为0.4 μM。我们还使用双电极电压钳、自动和手动膜片钳评估了BBP对一组钙激活和电压激活钾通道的选择性。BBP对IK、K2.1、K3.1 + K3.4、K1.5、K4.3/K2和K7.1/KCNE1电流没有任何影响，并且对所有SK通道亚型的效力分别比对大电导钙激活钾（BK）通道和人醚 - 去极化激活钾通道（hERG）高4.8倍和46倍。此外，我们能够确定H491是BBP对SK通道药理作用的关键氨基酸。从药物化学角度来看，BBP可作为设计新型和改进型SK抑制剂的起点。
