A new series of 1-deoxy-1-[(6-(4-(substituted-aminosulfonyl)phenyl)amino)carbonylamino-9H-purin-9-yl]-N-ethyl-beta-D-ribofuranuronamides (83-102) have been synthesized and tested at the human A3 adenosine receptor subtype. All the derivatives described in this work displayed affinity versus this receptor in the nanomolar range and good selectivity versus A1 adenosine receptor subtype, confirming that the p-sulfonamido moiety positively affected the activity of the molecules. The best substituents at the sulfonamido nucleus were found to be small alkyl groups, like methyl, isopropyl, ethyl, or allyl moieties (compounds 96-100), whereas monosubstitution at the amino group led to a decrease in A3 affinity values. The selectivity versus A1 adenosine receptor subtype is increased when the amino group in the sulfonamido core is represented by a hydrogenated heterocyclic ring like piperidine, morpholine, or pyrroline. Bulky groups, like adamantane and alkyl chains with more than four carbon atoms, are detrimental for the affinity and the selectivity of the A3 adenosine receptor agonists described here.