Synthesis of 2-Chloro-N6-Substituted-4′-thioadenosine-5′-N, N-dialkyluronamides as Potent and Selective A3 Adenosine Receptor Antagonists

Abstract The highly selective A3 receptor agonist, 4′-thio-Cl-IB-MECA was successfully converted into selective A3 receptor antagonists by appending a second N-alkyl group on the 5′-uronamide position. This result indicates that the hydrogen bonding ability of the 5′-uronamide is essential for the conformational change required for the receptor activation. Among compounds tested, a N6-(3-bromobenzyl) derivative with 5′-dimethyluronamide exhibited the highest binding affinity (Ki = 9.32 nM) at the human A3 AR with very low binding affinities to other AR subtypes.