Synthesis of adenosine analogues with indole moiety as human adenosine A 3 receptor ligands.

Adenosine is an endogenous modulator exerting its functions through the activation of four adenosine receptor (AR) subtypes, termed A1 , A2A , A2B and A3 , which belong to the G-protein-coupled receptor superfamily. The human A3 AR (hA3 AR) subtype is implicated in several cytoprotective functions. Therefore, hA3 AR modulators, and in particular agonists, are sought for their potential application as anti-inflammatory, anti-cancer and cardioprotective agents. Here, we prepared novel adenosine derivatives with indole moiety as hA3 AR ligands. According to the biological assay, we found that 2-substituents 11 were critical structural determinants for A3 AR ligands ( K i  = 111 nM). The observed structure-affinity relationships of this class of ligands were also exhaustively rationalized using the molecular modelling approach. This allows the investigation on the binding mode of the potential compound in the ligand-binding pocket of the human A3 receptor. The results demonstrated that 11 can interact with the ASN250, GLN167, PHE168 and VAL178 through hydrogen bonding, which are shown to be important for ligand-receptor interaction.