Extracellular adenosine receptors have been divided into two major subtypes, called A1 and A2. Substitution of the adenosine molecule with appropriate groups at C2 or N6 is known to impart selectivity for the A2 receptor over the A1 receptor. In the present study, we investigated whether substitution at both C2 and N6 would have additive effects on the A2/A1 affinity ratio, thereby providing compounds with greater A2 selectivity than presently available agents. Disappointingly, additivity appeared to hold only when an A1-selective group was present at N6. For instance, 2-(phenylamino) substitution of the A1-selective agonist N6-cyclopentyladenosine resulted in a 70-fold shift in selectivity in favor of the A2 receptor, but the same substitution applied to the A2-selective agonist N6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl]adenosine resulted in a 100-fold loss of affinity with no change in A2 selectivity.