Supplementary material from "Synthesis of adenosine analogues with indole moiety as human adenosine A3 receptor ligands"

Adenosine is an endogenous modulator exerting its functions through the activation of four adenosine receptor (AR) subtypes, termed A₁, A_2A, A_2B and A₃, which belong to the G-protein-coupled receptor superfamily. The human A₃AR (hA₃AR) subtype is implicated in several cytoprotective functions. Therefore, hA₃AR 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 hA₃AR ligands. According to the biological assay, we found that 2-substituents 11 were critical structural determinants for A₃AR 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.