Adenosine and adenosine agonists have numerous physiological effects in the nervous system, including inhibition of neurotransmitter release, anticonvulsant activity, analgesia, respiratory depression, hypothermia, and profound decreases in locomotor activity.12 The receptors that mediate these responses have been studied indirectly through the responses that they elicit8,14 and directly by receptor binding methods.1,15 There are two main classes of extracellular adenosine receptors: A1 receptors whose activation leads to inhibition of adenylate cyclase and A2 receptors whose activation leads to stimulation of adenylate cyclase.14 These receptors are designated Ri and Ra, respectively, in an alternative nomenclature.8 Although N6-substituted adenosines, especially β-cyclohexyladenosine (CHA), are known to be selective A1 agonists1,13,15 and to possess activity as inhibitors of platelet aggregation7 and neurotransmission,9 structure-activity relationships for lower and higher homologues of CHA have not been explored to date. The present study reports the discovery of N6-cyclopentyladenosine (CPA) as a potent, A1-selective adenosine agonist, a finding that has allowed the development of an A2 receptor binding assay. Additionally, this study reports the binding affinities for a series of N6-cycloalkyladenosines at both A1 and A2 adenosine receptors.