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

Abstract

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 A3 adenosine receptor (AR), N 6-substituted purine analogues bound potently and selectively and acted as antagonists in a cyclic AMP functional assay. An N6-(3- chlorobenzyl)purine analogue 9b displayed a Ki value of 1.66 nM at the human A3 AR. Thus, truncated D-4′-thioadenosine is an excellent template for the design of novel A3 AR antagonists to act at both human and murine species. © 2007 American Chemical Society.