Discovery of a new nucleoside template for human A3 adenosine receptor ligands:: D-4′-thioadenosine derivatives without 4′-hydroxymethyl group as highly potent and selective antagonists

Truncated D-4'-thioadenosine derivatives lacking the 4'-hydroxymethylene moiety were synthesized starting from D-mannose, using cyclization to the 4-thiosugar and one-step conversion of the diol to the acetate as key steps. At the human A(3) adenosine receptor (AR), N(6)-substituted purine analogues bound potently and selectively and acted as antagonists in a cyclic AMP functional assay. An N(6)-(3-chlorobenzyl)purine analogue 9b displayed a K(i) value of 1.66 nM at the human A(3) AR. Thus, truncated D-4'-thioadenosine is an excellent template for the design of novel A(3) AR antagonists to act at both human and murine species.