5‘-Deoxy Congeners of 9-(3-Amido-3-deoxy-β-d-xylofuranosyl)-N⁶-cyclopentyladenine:  New Adenosine A₁ Receptor Antagonists and Inverse Agonists

The synthesis and structure−activity relationship of N⁶-cyclopentyl-3‘-substituted-xylofuranosyladenosine analogues with respect to various adenosine receptors were explored in order to identify selective and potent antagonists and inverse agonists for the adenosine A₁ receptor. In particular, the effects of removal of the 5‘-OH group and introduction of selected substituents at the 3‘-NH₂ position of 9-(3-amino-3-deoxy-β-d-xylofuranosyl)-N⁶-cyclopentyladenine were probed. A solid phase-assisted synthetic approach was used to optimize the 3‘-amide functionality. In view of the general concern of the presence of a 5‘-OH moiety with regard to cellular toxicity, the present study describes 5‘-deoxy compounds with reasonable affinity for the human adenosine A₁ receptor. Interestingly, this study shows that optimization of the 3‘-“up” amide sustituent can substantially compensate for the drop in affinity for the adenosine A₁ receptor, which is generally observed upon removal of the 5‘-OH group. The fact that for several 3‘-amido-substituted (5‘-deoxy)-N⁶-cyclopentyladenosine derivatives, guanosine 5‘-triphosphate-induced shifts in K_i values were significantly lower than 1 implies that these analogues behave as inverse agonists. This is further supported by their 1,3-dipropyl-8-cyclopentylxanthine-like capacity to increase forskolin-induced adenosine cyclic 3‘,5‘-phosphate production.