N6-Cyclosubstituted isoguanosines have been synthesized in high yields from 2-amino-6-chloropurine ribonucleoside. Compounds containing five- and six-membered rings at the N6-position exhibit high adenosine A1 receptor affinity and excellent A2/A1 selectivity. The natural nucleoside, adenosine, apparently exerts many of its physiological effects through the involvement of extracellular receptors referred to as A1 and A2 which are distributed throughout a wide variety of tissues in the human system. The A1 and A2 receptors have been associated with a decrease or an increase, respectively, of intracellular levels of cyclic AMP. Adenosine has been approved clinically for the treatment of paroxysmal supraventricular tachycardia; however, its therapeutic usefulness is limited by poor receptor selectivity, and a very short metabolic lifetime because of its hydrolytic deamination by the ubiquitous mammalian enzyme, adenosine deaminase. The natural minor nucleoside, isoguanosine (2-hydroxyadenosine) has been reported to have hypotensive properties greater than adenosine and to be metabolically resistant to deamination by adenosine deaminase. There has been considerable interest in developing adenosine receptor agonists that have better pharmacological properties than adenosine both in terms of metabolic stability and in terms of A1, A2 receptor binding and specificity. Adenosine agonists with high selectivity for the A1 or A2 receptor are of potential interest as antiarrhythmics, anticonvulsants, antihypertensives and as other therapeutic agents. Several recent reports of highly active and selective nucleoside systems for both A1 and A2 receptors have focused attention on 2- and/or N6-modified adenosines. However, very few examples of agonists which are isoguanosine analogues are known. This communication reports on the synthesis and A1, A2 receptor binding activities of novel N6-cyclosubstituted isoguanosine compounds.