Structure-activity relationships of 2-chloro-N6-substituted- 4′-thioadenosine-5′-uronamides as highly potent and selective agonists at the human A3 adenosine receptor

Abstract

We have established structure-activity relationships of novel 4′-thionucleoside analogues as the A3 adenosine receptor (AR) agonists. Binding affinity, selectivity toward other AR subtypes, and efficacy in inhibition of adenylate cyclase were studied. From this study, 2-chloro-N 6-methyl-4′-thioadenosine-5′-methyluronamide (36a) emerged as the most potent and selective agonist at the human A3 AR. We have also revealed that, similar to 4′-oxoadenosine analogues, at least one hydrogen on the 5′-uronamide moiety was necessary for high-affinity binding at the human A3 AR, presumably to allow this group to donate a H bond within the binding site. Furthermore, bulky substituents on the 5′-uronamide reduced binding affinity, but in some cases large 5′-uronamide substituents, such as substituted benzyl and 2-phenylethyl groups, maintained moderate affinity with reduced efficacy, leading to A 3 AR partial agonists or antagonists. In several cases for which the corresponding 4′-oxonucleosides have been studied, the 4′-thionucleosides showed higher binding affinity to the A3 AR. © 2006 American Chemical Society.