Naphtho[1,2-d]thiazol-2-ylamine (SKA-31), a new activator of KCa2 and KCa3.1 potassium channels, potentiates the endothelium-derived hyperpolarizing factor response and lowers blood pressure.
Naphtho[1,2-d]thiazol-2-ylamine (SKA-31), a new activator of KCa2 and KCa3.1 potassium channels, potentiates the endothelium-derived hyperpolarizing factor response and lowers blood pressure.
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DOI：
10.1124/mol.108.051425
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发表时间：
2009-02
影响因子：
3.6
通讯作者：
Wulff, Heike
中科院分区：
文献类型：
--
作者：
Sankaranarayanan, Ananthakrishnan;Raman, Girija;Busch, Christoph;Schultz, Tim;Zimin, Pavel I.;Hoyer, Joachim;Koehler, Ralf;Wulff, Heike
小电导（KCa2.1-2.3）和中电导（KCa3.1）钙激活的K+通道在调节可兴奋和不可兴奋细胞中的钙信号级联和膜电位中起关键作用。这些通道的激活剂构成有用的药理学工具以及用于治疗共济失调、癫痫和高血压的潜在新药。我们在这里使用的神经保护剂利鲁唑作为模板的KCa 2/3通道激活剂的设计是足够有效的体内研究。从41种苯并噻唑化合物中，我们鉴定出两种化合物，SKA-20（蒽[2，1-d]噻唑-2-基胺）和SKA-31（萘并[1，2-d]噻唑-2-基胺），效力是利鲁唑的10-20倍，激活KCa 2.1的EC 50为430 nM和2.9 μM，激活KCa 2.2的EC 50为1.9 μM，KCa 2.3的EC 50分别为1.2 μM和2.9 μM，KCa 3.1的EC 50分别为115 nM和260 nM。同样，SKA-20和SKA-31激活了鼠内皮细胞中的天然KCa2.3和KCa3.1通道，而更“药物样”的SKA-31（半衰期12小时）增强了KCa3.1+/+小鼠（但不是KCa3.1 −/−小鼠）的内皮源性超极化因子介导的颈动脉扩张。10和30 mg/kg SKA-31给药使血压正常小鼠的平均动脉血压降低4和6 mmHg，使血管紧张素II诱导的高血压降低12 mmHg。这些作用在KCa3.1缺陷小鼠中不存在。总之，SKA-31设计了一种新的药理学工具来定义体内KCa 2/3通道激活的功能作用。SKA-31的降血压作用提示KCa 3.1通道激活是治疗高血压的新的治疗原则。
Small-conductance (KCa2.1-2.3) and intermediate-conductance (KCa3.1) calcium-activated K+ channels are critically involved in modulating calcium-signaling cascades and membrane potential in both excitable and non-excitable cells. Activators of these channels constitute useful pharmacological tools as well as potential new drugs for the treatment of ataxia, epilepsy, and hypertension. We here used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Out of a library of 41 benzothiazoles we identified two compounds, SKA-20 (anthra[2,1-d]thiazol-2-ylamine) and SKA-31 (naphtho[1,2-d]thiazol-2-ylamine), which are 10–20 times more potent than riluzole and activate KCa2.1 with EC50s of 430 nM and 2.9 μM, KCa2.2 with EC50s of 1.9 μM, KCa2.3 with EC50s of 1.2 μM and 2.9 μM, and KCa3.1 with EC50s of 115 nM and 260 nM. Likewise, SKA-20 and SKA-31 activated native KCa2.3 and KCa3.1 channels in murine endothelial cells and the more “drug-like” SKA-31 (half-life 12 hours) potentiated endothelium-derived hyperpolarizing factor-mediated dilations of carotid arteries from KCa3.1+/+ mice but not from KCa3.1−/− mice. Administration of 10 and 30 mg/kg SKA-31 lowered mean arterial blood pressure by 4 and 6 mmHg in normotensive mice and by 12 mmHg in angiotensin-II-induced hypertension. These effects were absent in KCa3.1-deficient mice. In conclusion, with SKA-31 we have designed a new pharmacological tool to define the functional role of KCa2/3 channel activation in vivo. The blood pressure lowering effect of SKA-31 suggests KCa3.1 channel activation as a new therapeutic principle for the treatment of hypertension.
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影响因子：
7.3
作者：
Eichler, I;Wibawa, J;Köhler, R
通讯作者：
Köhler, R
影响因子：
64.8
作者：
Edwards, G;Dora, KA;Weston, AH
通讯作者：
Weston, AH
DOI：
10.1016/j.jchromb.2004.01.004
发表时间：
2004-04-25
影响因子：
3
作者：
Colovic, M;Zennaro, E;Caccia, S
通讯作者：
Caccia, S
影响因子：
3.8
作者：
Liu, Yuhong;Sellke, Eric W.;Feng, Jun;Clements, Richard T.;Sodha, Neel R.;Khabbaz, Kamal R.;Senthilnathan, Venkatachalam;Alper, Seth L.;Sellke, Frank W.
通讯作者：
Sellke, Frank W.
影响因子：
3.3
作者：
Ahn, HS;Choi, JS;Hahn, SJ
通讯作者：
Hahn, SJ