New 2,N6-Disubstituted adenosines: Potent and selective A1 adenosine receptor agonists

A number of adenosine analogues substituted in the 2- and <i>N⁶</i>-positions were synthesized and evaluated for affinity, functional potency and intrinsic activity at the<i> A₁</i> and<i> A₂_A</i> adenosine receptors (<i>AR</i>). Three classes of <i>N⁶</i>-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 <i>A₁AR</i> and high potency for inhibiting (−)isoproterenol-stimulated cAMP accumulation in hamster smooth muscle DDT1 MF-2 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 21680 was dependent upon the halogen substituent in the C-2 position with most showing partial agonist activity. Of particular interest is 2-iodo-<i>N⁶</i>-(2S-endo-norborn-2-yl)adenosine (<b>5e</b>), which is over 100-fold selective for the <i>A₁AR</i>, is a full agonist at this receptor subtype and has no detectable agonist activity at the <i>A_2AAR</i>.<br />