Structure–activity relationships of truncated adenosine derivatives as highly potent and selective human A 3 adenosine receptor antagonists

Abstract

On the basis of potent and selective binding affinity of truncated 4′-thioadenosine derivatives at the human A 3 adenosine receptor (AR), their bioisosteric 4′-oxo derivatives were designed and synthesized from commercially available 2,3- O-isopropylidene- d-erythrono lactone. The derivatives tested in AR binding assays were substituted at the C2 and N 6 positions. All synthesized nucleosides exhibited potent and selective binding affinity at the human A 3 AR. They were less potent than the corresponding 4′-thio analogues, but showed still selective to other subtypes. The 2-Cl series generally were better than the 2-H series in view of binding affinity and selectivity. Among compounds tested, compound 5d (X = Cl, R = 3-bromobenzyl) showed the highest binding affinity ( K i = 13.0 ± 6.9 nM) at the hA 3 AR with high selectivity (at least 88-fold) in comparison to other AR subtypes. Like the corresponding truncated 4′-thio series, compound 5d antagonized the action of an agonist to inhibit forskolin-stimulated adenylate cyclase in hA 3 AR-expressing CHO cells. Although the 4′-oxo series were less potent than the 4′-thio series, this class of human A 3 AR antagonists is also regarded as another good template for the design of A 3 AR antagonists and for further drug development.