The structure–activity relationships of 63 adenosine analogs as agonists for the A1 adenosine receptors that mediate inhibition of adenylate cyclase activity in rat fat cells and for the A2 adenosine receptors that mediate stimulation of adenylate cyclase in rat pheochromocytoma PC12 cells and human platelets were determined. The lack of correspondence between the structure–activity relationships of these analogs at the A1 and A2 receptors appear definitive in terms of establishing the existence of A1 and A2 subclasses of adenosine receptors. However, significant differences in the agonist profiles at A2 receptors of platelet and PC12 indicate a certain degree of structural heterogeneity within the members of the A2 adenosine receptor subclass. Whether such differences are due to different species or different cell types is not known. A set of adenosine analogs, such as N6-cyclohexyl-, N6-R-, and S-1-phenyl-2- propyladenosines, 5′-N-ethylcarboxamidoadenosine and its N6-cyclohexyl derivative, 2-chloro- adenosine, and 2-phenylaminoadenosine, appear to represent a series of analogs useful for pharmacological characterization of A1 and A2 classes of adenosine receptors.
Adenosine receptors: pharmacology, structure-activity relationships, and therapeutic potential