Synthesis, biological activity and molecular modelling of new trisubstituted 8-azaadenines with high affinity for A(1) adenosine receptors

We describe here the synthesis and biological activity of new 8-azaadenines bearing both a phenyl group on C(2) and a 9-benzyl group substituted in the ortho position with a Cl or a F atom or a CF3 group, to verify the synergistic effect of a combination of these substitution patterns on binding with the A1 adenosine receptors. In position N6 aliphatic and cycloaliphatic substituents were chosen which had been shown to bind well with the A1 receptors. Because of the high lipophilicity of these kinds of molecules, we also introduced a hydroxyalkyl substituent in the same position. The compounds obtained generally showed a very good affinity and selectivity for A1 receptors. Some of the compounds showed Ki in the nanomolar range, one even in the subnanomolar range (0.6 nM). Molecular docking calculations were performed in order to evaluate the interaction energies between the bovine A1 receptor model and the selected ligands, and then to correlate these energies with biological activities of the ligands as obtained from the experiments. Molecular docking analysis suggests different binding modes towards A1 receptors that are plausible for these ligands.