Figure 1.

The design of the target nucleosides acting dually at the A_2A and A₃ARs A molecular modeling study⁸ indicated that the NH of the 5′-uronamide of 1 serves as a hydrogen bonding donor in the A₃AR binding site and is associated with the induced fit for the receptor activation. On this basis, we designed and synthesized truncated adenosine derivatives 2⁹ removing the 5′-uronamide of 1, to bind potently but with altered ability to induce the conformational change essential for receptor activation. As expected, members of the series of compound 2 proved to be potent and selective A₃AR antagonists.⁹ It should be noted that these A₃AR antagonists 2 also showed species-independent binding affinity, making them suitable for efficacy evaluation for drug development in small animal models.⁹ Compound 2 (X = S, R = 3-iodobenzyl) exhibited a potent anti-glaucoma effect in vivo.¹⁰