Design, Synthesis, and Structure−Activity Relationships of 1-,3-,8-, and 9-Substituted-9-deazaxanthines at the Human A_2B Adenosine Receptor

Over two hundred 1-, 3-, 8-, and 9-substituted-9-deazaxanthines were prepared and evaluated for their binding affinity at the recombinant human adenosine receptors, in particular at the hA_2B and hA_2A subtypes. Several ligands endowed with sub-micromolar to low nanomolar binding affinity at hA_2B receptors, good selectivity over hA_2A and hA₃, but a relatively poor selectivity over hA₁ were obtained. Good antagonistic potencies and efficacies, with pA₂ values close to the corresponding pK_is, were observed in functional assays in vitro performed on a selected series of compounds. 1,3-Dimethyl-8-phenoxy-(N-p-halogenophenyl)-acetamido-9-deazaxanthine derivatives appeared as the most interesting leads, some of them showing outstanding hA_2B affinities, high selectivity over hA_2A and hA₃, but low selectivity over hA₁. Structure−affinity relationships suggested that the binding potency at the hA_2B receptor was mainly modulated by the steric (lipophilic) properties of the substituents at positions 1 and 3 and by the electronic and lipophilic characteristics of the substituents at position 8. A comparison among affinity and selectivity profiles of 9-deazaxanthines with the corresponding xanthines suggested some possible differences in their binding mode.