Design, synthesis and biological evaluation of selective antagonists for the various adenosine receptors

Adenosine is a signaling substance, which mediate its effects by activation of fours different G-protein-coupled receptors (GPCR) (A1, A2A, A2B and A3). The receptors differs in their affinity for adenosine as well as their downstream signaling pathways a ctivated in the target cells. The ARs are present in basically every cell in the body, but their abundance in different tissue varies. Adenosine has very limited applications as a drug due to an extremely short half-life (t1/2 < 10 s). Caffeine and theoph ylline are classical non-selective AR antagonist with high affinities for A1 and A2A receptors. The excitatory effects of caffeine are a result of its ability to antagonize adenosine activity at A1 receptors in the central nervous system. A selective and potent ligand for any of the ARs may have a drug potential, i.e. A1 antagonists for treatment of asthma, A2A antagonists as anti-Parkinson drugs, A2B antagonists for treatment of chronic pulmonary diseases and A3 antagonists as anti-cancer agents. We have recently initiated screening of a small library of 6-arylpurines examined by us earlier as selective inhibitors of Mycobacterium tuberculosis. From the results currently available, it is clear that minor structural changes may lead to compounds with comp letely altered selectivity, and we believe, that potent and selective antagonists of all four AR sub-types will be synthesized in the planned project. Synthesis of optimized structures with respect to potency and AR sub-type selectivity will be carried ou t at the University of Oslo, and target compounds will be designed based on available screening results, molecular modeling and drug-like physiochemical properties. Biological evaluations as adenosine receptor ligands in the group of Prof. Christa Müller, University of Bonn and molecular modeling may be conducted in cooperation with Prof. Müller and collaborators at the University of Bonn and the Fraunhofer Inst. St. Augustin.