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

Abstract

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 (Ki = 9.32 nM) exhibited the highest binding affinity at the human A3AR with very low binding affinities to other AR subtypes. © 2008 Elsevier Ltd. All rights reserved.