Synthesis of hypermodified adenosine derivatives as selective adenosine A3 receptor ligands

We investigated the A3AR affinity and selectivity of a series of 2-substituted 3′-azido and 3′-amino adenosine derivatives as well as some 5′-uronamide derivatives thereof. All compounds showed high A3AR selectivity. While the 3′-azides appeared to be A3AR antagonists with moderate A3AR affinity, their 3′-amino congeners exhibit significantly improved A3AR affinity and behave as partial agonists. For both the 3′-azides and the 3′-amines, the 5′-methylcarbamoyl modification improved the overall affinity. Introduction of a 2-phenylethynyl substituent provided high affinity for the A3AR.