Discovery of Potential, Dual-Active Histamine H3 Receptor Ligands with Combined Antioxidant Properties

In an attempt to find new dual acting histamine H-3 receptor (H3R) ligands, we designed a series of compounds, structurally based on previously described in our group, a highly active and selective human histamine H-3 receptor (hH(3)R) ligand KSK63. As a result, 15 obtained compounds show moderate hH(3)R affinity, the best being the compound 17 (hH(3)R K-i = 518 nM). Docking to the histamine H3R homology model revealed two possible binding modes, with key interactions retained in both cases. In an attempt to find possible dual acting ligands, selected compounds were tested for antioxidant properties. Compound 16 (hH(3)R K-i = 592 nM) showed the strongest antioxidant properties at the concentration of 10(-4) mol/L. It significantly reduced the amount of free radicals presenting 50-60% of ascorbic acid activity in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, as well as showed antioxidative properties in the ferric reducing antioxidant power (FRAP) assay. Despite the yet unknown antioxidation mechanism and moderate hH(3)R affinity, 16 (QD13) constitutes a starting point for the search of potential dual acting H3R ligands-promising tools for the treatment of neurological disorders associated with increased neuronal oxidative stress.

Automated summary

Researchers designed a series of dual acting histamine H-3 receptor ligands, with compound 16 demonstrating strong antioxidant properties and moderate hH(3)R affinity. These compounds could serve as potential tools for treating neurological disorders.