Adenosine Agonists and Antagonists

Abstract

The modern era of research on the nature of adenosine receptors began in the early seventies. At that time the stimulatory effect of adenosine on formation of cyclic AMP in brain slices and blockade by xanthines, such as caffeine and theophylline, was discovered (Sattin and Rall, 1979). The class of adenosine receptors that are coupled to adenylate cyclase in an inhibitory manner have become known as A₁-receptors, while the class of adenosine receptors that are coupled to adenylate cyclase in a stimulatory manner have become known as A₂-receptors. The rank order of potencies for certain agonists differed at A₁- and A₂-receptors and it was suggested that rank order of potencies at 5’-N’ ethylcarboxamidoadenosine (NECA), 2-chloroadenosine, N⁶-R-phenylisopropyladenosine and N₆-S-phenylisopropyladenosine might be useful for definition of the class of adenosine receptor involved in physiological responses (see Daly, 1982). This series of agonists has not proven to be entirely satisfactory and more definitive series of selective agonists and antagonists have been and are being sought. The lack of complete correspondence of rank orders of potencies of agonists in certain physiological systems to that expected of A₁ receptors coupled to adenylate cyclase has led to the proposal of an A₃-receptor, which is localized in presynaptic nerve terminals and which serves to inhibit neurotransmitter release (Ribeiro and Sebastião, 1986). In the synaptic terminals a variety of evidence suggests that the receptor is coupled not to adenylate cyclase, but instead in an inhibitory manner to calcium channels or calcium function. There also is evidence for adenosine receptors that are coupled in a stimulatory manner to potassium channels in brain and heart (see Fredholm and Dunwiddie, 1988). At present the adenosine receptors coupled to calcium and potassium channels are perhaps best still treated as subclasses of A₁ receptors, since unambiguous paradigms for distinguishing these receptors from A₁ receptors coupled to adenylate cyclase have not been developed.