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

作者：Matos Maria J^*; Vilar Santiago; Kachler Sonja; Celeiro Maria; Vazquez Rodriguez Saleta; Santana Lourdes; Uriarte Eugenio; Hripcsak George; Borges Fernanda; Klotz Karl Norbert

来源：Bioorganic Chemistry, 2015, 61: 1-6.

DOI：10.1016/j.bioorg.2015.05.008

• 3-Amidocoumarins
• Adenosine ligands
• Theoretical ADME properties
• Molecular modeling calculations

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 (A(1), A(2A) and A(3)) and adenylyl cyclase activity (A(2B)) 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 A(3) AR (K-i = 3.24 mu M). The current study supported that small structural changes in this scaffold allowed modulating the affinity resulting in novel promising classes of A(1), A(2A), and/or A(3) AR ligands. We also performed docking calculations in hA(2A) and hA(3) 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.

• 出版日期2015-8