Structure−Activity Relationships of 2-Chloro-N6-substituted-4‘-thioadenosine-5‘-uronamides as Highly Potent and Selective Agonists at the Human A3 Adenosine Receptor

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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-N6-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 A3 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.