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. Crown Copyright (C) 2013 Published by Elsevier Ltd. All rights reserved.