Synthesis and molecular docking of novel non-competitive antagonists of GluK2 receptor

Abstract

Here we present the synthesis, pharmacological activity, and molecular docking of novel non-competitive antagonists of GluK2 receptor. The compounds concerned are derivatives of indole and carbazole and are the second reported series of non-competitive antagonists of the GluK2 receptor (the first one was also published by our group). The activity of the indole derivatives is in the micromolar range, as in the case of the first series of non-competitive GluK2 receptor antagonists. We have found that designed carbazole derivatives are devoid of activity. Active indole derivatives interact with the transduction domain of the GluK2 receptor, i.e., the domain which links the transmembrane region of the receptor with the agonist-binding domain. The binding pocket is situated within one receptor subunit.

Thermal and spectroscopic studies of 2,3,5-trisubstituted and 1,2,3,5-tetrasubstituted indoles as non-competitive antagonists of GluK1/GluK2 receptors

“…In particular, a non-competitive mode of action can result in a better safety profile as reported for non-competitive antagonists of a-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid (AMPA) receptors [19]. In the previous studies, we also constructed 3D models of GluK1 and GluK2 receptors and suggested that indolederived non-competitive antagonists can bind in the receptor transduction domain [11,14,15,20,21]. In this study, in order to investigate thermal behaviour of indole derivatives the TG-DSC and TG-FTIR methods were applied.…”

“…These compounds are a noncompetitive antagonists of kainate GluK1/GluK2 (GluKglutamatergic kainate receptors) receptors with low micromolar activity, and compound 2 is the most promising from the series [10,11]. Non-competitive antagonists of kainate receptors [10][11][12][13][14][15] can be considered promising compounds for the treatment of neurodegenerative diseases [16,17] as well as epilepsy [18]. In particular, a non-competitive mode of action can result in a better safety profile as reported for non-competitive antagonists of a-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid (AMPA) receptors [19].…”