Discovery of a new human A_2A adenosine receptor agonist, truncated 2-hexynyl-4′-thioadenosine

The truncated C2- and C8-substituted 4′-thioadenosine derivatives 4a-d were synthesized from d-mannose, using palladium-catalyzed cross-coupling reactions as key steps. In this study, an A₃ adenosine receptor (AR) antagonist, truncated 4′-thioadenosine derivative 3, was successfully converted into a potent A_2A AR agonist 4a (K_i = 7.19 ± 0.6 nM) by appending a 2-hexynyl group at the C2-position of a derivative of 3 that was N⁶-substituted. However, C8-substitution greatly reduced binding affinity at the human A_2A AR. All synthesized compounds 4a-d maintained their affinity at the human A₃ AR, but 4a was found to be a competitive A₃ AR antagonist/A_2A AR agonist in cyclic AMP assays. This study indicates that the truncated C2-substituted 4′-thioadenosine derivatives 4a and 4b can serve as novel templates for the development of new A_2A AR ligands.