On the basis of a bioisosteric rationale, 4′-thionucleoside analogues of IB-MECA (N 6 -(3-Iodo-benzyl)-9-(5′-methylaminocarbonyl-β-d-ribofuranosyl)adenine), which is a potent and selective A 3 adenosine receptor (AR) agonist, were synthesized from d-gulonic acid γ-lactone. The 4′-thio analogue (5h) of IB-MECA showed extremely high binding affinity (K i =0.25nM) at the human A 3 AR and was more potent than IB-MECA (K i =1.4nM). Bulky substituents at the 5′-uronamide position, such as cyclohexyl and 2-methylbenzyl, in this series of 2-H nucleoside derivatives were tolerated in A 3 AR binding, although small alkyl analogues were more potent.