New 2,N⁶-disubstituted adenosines: Potent and selective A1adenosine receptor agonists

A number of adenosine analogues substituted in the 2- and N6-positions were synthesized and evaluated for affinity, functional potency and intrinsic activity at the A1and A2Aadenosine receptors (AR). Three classes of N6-substituents were tested; norbornen -2-yl (series 1), norborn-2-yl (series 2) and 5,6-epoxynorborn-2-yl (series 3). The halogens; fluoro, bromo, and iodo were evaluated as C-2 substituents. All compounds showed relatively high affinity (nanomolar) for the A1AR and high potency for inhibiting (-) isoproterenol-stimulated cAMP accumulation in hamster smooth muscle DDT1MF2- cells with the 2-fluoro derivatives from each series having the highest affinity. All of the derivatives showed the same intrinsic activity as CPA. At the A2AAR, all of the derivatives showed relatively low affinity and potency (micromolar) for stimulating cAMP accumulation in rat pheochromocytoma PC-12 cells. The intrinsic activity of the derivatives compared to CGS 1680 was dependent upon the halogen substituent in the C-position with most showing partial agonist activity. Of particular interest is 2-iodo-N6-(2S-endo-norborn-2-yl) adenosine (5e), which is over 100-fold selective for the A1AR, is a full agonist at this receptor subtype and has no detectable agonist activity at the A2AAR. Copyright © 2002 Elsevier Science Ltd.