Adenosine regulates a wide range of physiological functions through interaction with at least two major classes of adenosine receptors. The A1 class of adenosine receptors is inhibitory to adenylate cyclase, while the A2 class is stimulatory to adenylate cyclase. Subclasses of adenosine receptors also occur. Some of these are inhibitory to calcium channels, some are stimulatory to potassium channels, some can activate guanylate cyclase, some can modulate phospholipid, while those of smooth muscle cause relaxation through a poorly defined mechanism. In the central nervous system activation of adenosine receptors caused behavioral depression, while blockade of adenosine receptors excitation. Activation by selective agonists of the central A1 and A2 receptors had synergistic depressant effects on locomotor activity in mice. Structure activity relationships at A1 and A2 adenosine receptors have been analyzed for various agonists and antagonists using binding and adenylate cyclase assays. The agonists included N6-substituted 2-chloroadenosines, 5'-substituted adenosine analogs, 3,4-dehydro-NECAs, 8,5'-O-anhydroadenosines and various 2-0-alkoxy and 2-0-aryloxyadenosines. The last class were potent and selective for A2A adenosine receptors. 5'-Methylthioadenosine and 5'-chloroadenosine were found to be agonists at A1 receptors, while having no or only partial agonist activity at A2 receptors. The antagonists included pyrazolopyridines related to the anxiolytic catazolate, 8-substituted xanthines and a wide range of caffeine analogs. Cultured PC12 cells, a widely used model system for investigation of A2 receptors, were found to contain mainly high affinity A2A receptors, but also low affinity of agonists and antagonists. Fibroblast 3T3 cells contained only A2B receptors, which exhibited the characteristic low affinity of this receptor for agonists, while affinities for antagonists was similar to affinities at A2A receptors. Certain xanthines inhibited antigen-binding to IgE in mast cells and thereby blocked antigen-induced responses.
