5-(Indol-2-yl)pyrazolo[3,4-b]pyridines as a New Family of TASK-3 Channel Blockers: A Pharmacophore-Based Regioselective Synthesis.

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.

In Silico Repositioning of Dopamine Modulators with Possible Application to Schizophrenia: Pharmacophore Mapping, Molecular Docking and Molecular Dynamics Analysis.

We have performed theoretical calculations with 70 drugs that have been considered in 231 clinical trials as possible candidates to repurpose drugs for schizophrenia based on their interactions with the dopaminergic system. A hypothesis of shared pharmacophore features was formulated to support our calculations. To do so, we have used the crystal structure of the D2-like dopamine receptor in complex with risperidone, eticlopride, and nemonapride. Linagliptin, citalopram, flunarizine, sildenafil, minocycline, and duloxetine were the drugs that best fit with our model. Molecular docking calculations, molecular dynamics outcomes, blood-brain barrier penetration, and human intestinal absorption were studied and compared with the results. From the six drugs selected in the shared pharmacophore features input, flunarizine showed the best docking score with D2, D3, and D4 dopamine receptors and had high stability during molecular dynamics simulations. Flunarizine is a frequently used medication to treat migraines and vertigo. However, its antipsychotic properties have been previously hypothesized, particularly because of its possible ability to block the D2 dopamine receptors.