1,3-Dialkyl-8-N-substituted benzyloxycarbonylamino-9-deazaxanthines as potent adenosine receptor ligands: Design, synthesis, structure–affinity and structure–selectivity relationships

Abstract

A number of 1,3-dialkyl-9-deazaxanthines (9-dAXs), bearing a variety of N-substituted benzyloxycarbonylamino substituents at position 8, were prepared and evaluated for their binding affinity to the recombinant human adenosine receptors ( hARs), chiefly to the hA 2B and hA 2A AR subtypes. Several ligands endowed with excellent binding affinity to the hA 2B receptors, but low selectivity versus hA 2A and hA 1 were identified. Among these, 1,3-dimethyl- N-3′-thienyl carbamate 15 resulted as the most potent ligand at hA 2B ( K i = 0.8 nM), with a low selectivity versus hA 2A ( hA 2A/ hA 2B = 12.6) and hA 1 ( hA 1/ hA 2B = 12.5) and a higher selectivity versus hA 3 ( hA 3/ hA 2B = 454). When tested in functional assays in vitro, compound 15 exhibited high antagonist activities and efficacies versus both the A 2A and A 2B receptor subtypes, with pA 2 values close to the corresponding p K is. A comparative analysis of structure–affinity and structure–selectivity relationships of the similar analogues 8-N-substituted benzyloxycarbonylamino- and 8-N-substituted phenoxyacetamido-9-dAXs suggested that their binding modes at the hA 2B and hA 2A ARs may strongly differ. Computational studies help to clarify this striking difference arising from a simple, albeit crucial, structural change, from CH 2OCON to OCH 2CON, in the para-position of the 8-phenyl ring.