Novel adenosine A2A receptor ligands: A synthetic,functional and computational investigation of selected literature adenosine A2A receptor antagonists for extending into extracellular space

Growing evidence has suggested a role in targeting the adenosine A_2A receptor for the treatment of Parkinson’s disease. The literature compounds KW 6002 (2) and ZM 241385 (5) were used as a starting point from which a series of novel ligands targeting the adenosine A_2A receptor were synthesized and tested in a recombinant human adenosine A_2A receptor functional assay. In order to further explore these molecules, we investigated the biological effects of assorted linkers attached to different positions on selected adenosine A_2A receptor antagonists, and assessed their potential binding modes using molecular docking studies. The results suggest that linking from the phenolic oxygen of selected adenosine A_2A receptor antagonists is relatively well tolerated due to the extension towards extracellular space, and leads to the potential of attaching further functionality from this position.