Development of novel adenosine receptor ligands based on the 3-amidocoumarin scaffold.

With the aim of finding new adenosine receptor (AR) ligands presenting the 3-amidocoumarin scaffold, a study focusing on the discovery of new chemical entities was carried out. The synthesized compounds 1-8 were evaluated in radioligand binding (A1, A2A and A3) and adenylyl cyclase activity (A2B) assays in order to determine their affinity for human AR subtypes. The 3-benzamide derivative 4 showed the highest affinity of the whole series and was more than 30-fold selective for the A3 AR (Ki=3.24 μM). The current study supported that small structural changes in this scaffold allowed modulating the affinity resulting in novel promising classes of A1, A2A, and/or A3 AR ligands. We also performed docking calculations in hA2A and hA3 to identify the hypothetical binding mode for the most active compounds. In addition, some ADME properties were calculated in order to better understand the potential of these compounds as drug candidates.