Recent improvements in the field of A(3) adenosine receptor ligands

Adenosine regulates many physiol. functions via specific cell membrane receptors. To date, four adenosine receptor subtypes have been cloned, A1, A2A, A2B and A3, each of which exhibits a unique tissue distribution, ligand affinity and signal transduction mechanism. The pathophysiol. role of the A3 receptor might be very different from that of the A1 and A2A subtypes, in that A3 receptors could act as endogenous regulators under conditions of more severe challenge. To fully evaluate the biol. role of these receptors, subtype-selective agonists and antagonists with high affinity are required. Although most of the available ligands are only moderately selective for human A3 receptors, they have been useful probes to elucidate the function of this receptor subtype and have suggested a role for A3 receptors in inflammation, neurodegeneration, asthma and cardiac ischemia. Indeed, A3 receptor antagonists have been hypothesized to act as potential anti-asthmatic, anti-inflammatory or cerebroprotective agents. Moreover, A3 antagonists have been reported to induce apoptotic effects in some tumor cell lines at low concn., whereas A3 adenosine agonists appear to exert dual and opposite effects, either cytoprotective or cytotoxic, depending on the cell type and the level of receptor activation.