The activity of N6-cycloalkyl derivatives of adenosine, 2-chloroadenosine, 5'-chloroadenosine and N-ethylcarboximidoadenosine (NECA) and of 2-fluoroadenosine and 5-methylthioadenosines were compared at the A1-adenosine receptor inhibitory to adenylate cyclase in rat fat cell membranes and at the A2A-adenosine receptors stimulatory to adenylate cyclase in rat PC12 cell membranes. The N6-cycloalkyl derivatives in all cases were more potent (4- to 23-fold) than the parent compound at the A1 receptor, and were less potent (1.6- to 11-fold) than the parent compound at the A2A receptor. N6-Cyclopentyl-5'-chloroadenosine was the most selective agonist (900-fold) for the A1 receptor, while 2-fluoroadenosine was the only agonist with some selectivity (4.8-fold) for the A2A receptor. 5'-Methylthioadenosine was a weak agonist at both adenosine receptors. A 2-fluoro derivative of 5'-methylthioadenosine was somewhat more potent. Affinities of these analogs for inhibition of binding of radioligands to rat brain A1 and A2A receptors are presented.