Pyrazolo[4,3-e]1,2,4-Triazolo[1,5-c]Pyrimidine Ligands, New Tools to Characterize A3 Adenosine Receptors in Human Tumor Cell Lines

Increased concentrations of extracellular adenosine are reached in ischemic or inflamed tissues but have also been detected inside tumoral masses. If this finding may account for an important role of adenosine in the pathogenesis of tumors remains to be determined in view of its contradictory effects on cell survival and proliferation. In particular, adenosine was found to exert its effects on proliferation and on cell death mainly through the A3 adenosine receptor. Therefore, a complete pharmacological characterization of the subtype and number of the expressed A3 adenosine receptors is necessary for the elucidation of the role of adenosine via A3 receptors in a specific cell subtype. The lack of potent and selective radiolabelled A3 receptor antagonists has been, in the past, the major obstacle in the characterization of structure, function and regulation of this adenosine receptor subtype. Recently, our group has identified a series of substituted pyrazolotriazolopyrimidine derivatives as potent and selective antagonists to human A3 adenosine receptors. The most recent results obtained in this field will be summarized in the present review. Furthermore, the review will report the results of the biochemical and pharmacological characterization of A3 receptors in different human tumor cell lines and the multiple A3 receptor-sustained ways that could prime tumor development.