A3 adenosine receptor antagonists: History and future perspectives

The potential employment of selective A3 adenosine receptor (A3AR) antagonists in the therapeutic treatment of important pathologies, such as asthma, inflammation, neurodegeneration, glaucoma and cancer, is subject to intensive studies because of the considerable role of this receptor in a number of pathophysiological processes. A wide number of compounds exerting high potency and selectivity in antagonizing the hA 3 AR has been so far recognized being generally characterized by a remarkable structural diversity: nitrogen-containing aromatic monocyclic (thiazoles, thiadiazoles, 1,4-dihydropyridines, pyridines, 2- mercaptopyrimidines), bicyclic (flavonoid, isoquinoline, quinozalines, (aza)adenines), tricyclic systems (pyrazoloquinolines, triazoloquinoxalines, pyrazolotriazolopyrimidines, triazolopurines, tricyclic xanthines). The latest identification of nucleoside-derived antagonists, structurally related to the endogenous ligand, opened new frontiers for the elucidation of the therapeutic potential of this kind of ligands. Probably as a result of the enigmatic physiological role of A3AR, whose activation seems related to opposite effects concerning tissues protection in inflammatory and cancer cells, a few molecules have till now reached the preclinical investigation phase. © 2010 Springer Science+Business Media B.V.