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

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 hA2B and hA2A AR subtypes. Several ligands endowed with excellent binding affinity to the hA2B receptors, but low selectivity versus hA2A and hA1 were identified. Among these, 1,3-dimethyl-N-3′-thienyl carbamate 15 resulted as the most potent ligand at hA2B (Ki = 0.8 nM), with a low selectivity versus hA2A (hA2A/hA2B = 12.6) and hA1 (hA1/hA2B = 12.5) and a higher selectivity versus hA3 (hA3/hA2B = 454). When tested in functional assays in vitro, compound 15 exhibited high antagonist activities and efficacies versus both the A2A and A2B receptor subtypes, with pA2 values close to the corresponding pKis. 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 hA2B and hA2A ARs may strongly differ. Computational studies help to clarify this striking difference arising from a simple, albeit crucial, structural change, from CH2OCON to OCH2CON, in the para-position of the 8-phenyl ring.

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