Abstract
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.
Highlights
Leak or background two-pore domain potassium (K2P ) channels are a superfamily of proteins that selectively modulate the flow of potassium (K+ ) ions across the plasma membrane of living cells
According to our pharmacophore-based structural design and regioselective synthetic protocol of our hit compounds, we demonstrated that the ultrasound irradiation (USI) method can be used to synthesize larger libraries of derivatives under ultrasound-assisted conditions to expand the chemical space of our pyrazolo[3,4-b]pyridine compounds as novel hTASK-3 channel blockers
We have first discovered that pyrazolo[3,4-b]pyridines are a new emerging family of TASK-3 channel blockers
Summary
Leak or background two-pore domain potassium (K2P ) channels are a superfamily of proteins that selectively modulate the flow of potassium (K+ ) ions across the plasma membrane of living cells. Homeostasis in the inner ear) [4] Their expression is up- and downregulated in different cancer cells [5], suggesting a wide spectrum of functions to these channels [6], including, but not limited to cell signaling, behavior [1], normal hearing [4], breathing control [7], anesthesia [8], and tumorigenesis [5]. These aspects provide unique attributes to this superfamily of proteins as potential druggable targets for drug discovery [6]. Protein sequence analyses and homology modeling of TASK-1, -3, -5, and the recently solved
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