Structure-activity relationships of 2-chloro-N⁶-substituted-4′-thioadenosine-5′-N,N-dialkyluronamides as human A₃ adenosine receptor antagonists

On the basis of potent and selective A₃ adenosine receptor (AR) antagonist, 2-chloro-N⁶-(3-iodobenzyl)-4′-thioadenosine-5′-N,N-dimethyluronamide, structure-activity relationships were studied for a series of 5′-N,N-dialkyluronamide derivatives, synthesized from d-gulonic γ-lactone. From this study, it was revealed that removal of the hydrogen bond-donating ability of the 5′-uronamide was essential for the pure A₃AR antagonism. 5′-N,N-Dimethyluronamide derivatives exhibited higher binding affinity than larger 5′-N,N-dialkyl or 5′-N,N-cycloalkylamide derivatives, indicating that steric factors are crucial in binding to the human A₃AR. A N⁶-(3-bromobenzyl) derivative 6c (K_i = 9.32 nM) exhibited the highest binding affinity at the human A₃AR with very low binding affinities to other AR subtypes.