التفاصيل البيبلوغرافية
| العنوان: |
5-(Indol-2-yl)pyrazolo[3,4- b ]pyridines as a New Family of TASK-3 Channel Blockers: A Pharmacophore-Based Regioselective Synthesis. |
| المؤلفون: |
Ramírez, David, Mejia-Gutierrez, Melissa, Insuasty, Braulio, Rinné, Susanne, Kiper, Aytug K., Platzk, Magdalena, Müller, Thomas, Decher, Niels, Quiroga, Jairo, De-la-Torre, Pedro, González, Wendy |
| المصدر: |
Molecules; Jul2021, Vol. 26 Issue 13, p3897-3897, 1p |
| مصطلحات موضوعية: |
MOLECULAR docking, MEMBRANE potential, CHEMICAL synthesis, CANCER cells, BIOACTIVE compounds |
| مستخلص: |
TASK channels belong to the two-pore-domain potassium (K2P) channels subfamily. These channels modulate cellular excitability, input resistance, and response to synaptic stimulation. TASK-channel inhibition led to membrane depolarization. TASK-3 is expressed in different cancer cell types and neurons. Thus, the discovery of novel TASK-3 inhibitors makes these bioactive compounds very appealing to explore new cancer and neurological therapies. TASK-3 channel blockers are very limited to date, and only a few heterofused compounds have been reported in the literature. In this article, we combined a pharmacophore hypothesis with molecular docking to address for the first time the rational design, synthesis, and evaluation of 5-(indol-2-yl)pyrazolo[3,4-b]pyridines as a novel family of human TASK-3 channel blockers. Representative compounds of the synthesized library were assessed against TASK-3 using Fluorometric imaging plate reader—Membrane Potential assay (FMP). Inhibitory properties were validated using two-electrode voltage-clamp (TEVC) methods. We identified one active hit compound (MM-3b) with our systematic pipeline, exhibiting an IC50 ≈ 30 μM. Molecular docking models suggest that compound MM-3b binds to TASK-3 at the bottom of the selectivity filter in the central cavity, similar to other described TASK-3 blockers such as A1899 and PK-THPP. Our in silico and experimental studies provide a new tool to predict and design novel TASK-3 channel blockers. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
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