General Aspects of Binding of Ligands to Adenosine Receptors

The concept of adenosine receptors has been developed from several independent lines of research. A first biochemical basis for the study of the molecular mechanisms of adenosine action was discovered when Sattin and Rall [1] and Shimizu et al. [2] described the potent stimulatory effects of adenosine and adenine nucleotides on cyclic AMP formation in brain slices. These authors proposed the existence of an external adenosine receptor that stimulates adenylate cyclase in a hormone-like manner and that is competitively inhibited by several methylxanthines. In other tissues, adenosine was found to inhibit adenylate cyclase-dependent reactions [3–5]. Based on these observations, two types of adenosine receptors have been classified by the use of selected adenosine analogues [6]. The inhibitory adenosine receptor has a high affinity for adenosine and has been designated Ri. The stimulatory adenosine receptor has a lower affinity for adenosine and has been designated Ra. An alternative nomenclature, using Al for the inhibitory receptor and A2 for the stimulatory receptor, has been proposed [5]. Moreover, nearly all cyclases contain an additional inhibitory P site located at the internal side of the cell membrane [7].