Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 nonexcitable cells. Activators of these channels constitute useful pharmacological tools and potential new drugs for the treatment of ataxia, epilepsy, and hypertension. Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC(50) values of 430 nM and 2.9 microM, KCa2.2 with an EC(50) value of 1.9 microM, KCa2.3 with EC(50) values of 1.2 and 2.9 microM, and KCa3.1 with EC(50) values of 115 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 of 12 h) 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 mm Hg in normotensive mice and by 12 mm Hg 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 the 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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PMID: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. 1895 85

Most cardiovascular researchers are familiar with intermediate-conductance KCa3.1 and small-conductance KCa2.3 channels because of their contribution to endothelium-derived hyperpolarization. However, to immunologists and neuroscientists, these channels are primarily known for their role in lymphocyte activation and neuronal excitability. KCa3.1 is involved in the proliferation and migration of T cells, B cells, mast cells, macrophages, fibroblasts, and dedifferentiated vascular smooth muscle cells and is, therefore, being pursued as a potential target for use in asthma, immunosuppression, and fibroproliferative disorders. In contrast, the 3 KCa2 channels (KCa2.1, KCa2.2, and KCa2.3) contribute to the neuronal medium afterhyperpolarization and, depending on the type of neuron, are involved in determining firing rates and frequencies or in regulating bursting. KCa2 activators are accordingly being studied as potential therapeutics for ataxia and epilepsy, whereas KCa2 channel inhibitors like apamin have long been known to improve learning and memory in rodents. Given this background, we review the recent discoveries of novel KCa3.1 and KCa2.3 modulators and critically assess the potential of KCa activators for the treatment of diabetes and cardiovascular diseases by improving endothelium-derived hyperpolarizations.
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PMID:Endothelial small-conductance and intermediate-conductance KCa channels: an update on their pharmacology and usefulness as cardiovascular targets. 2310 76