CONCISE ARTICLE

摘要: We report the synthesis and pharmacological characterization of a new series of adenosine derivatives on the four adenosine receptors (ARs). In radioligand binding assays, some of the compounds (1, 4, 6 and (R)-6) display a potent affinity for the A2AAR (Ki values< 10 nM) with high A1/A2A and A2B/A2A selectivity, moderate for the A3AR and low for the A1AR. The affinity of the epimeric mixture 6 was similar to that of the corresponding (R)-6 stereoisomer and 10-fold higher than that of the (S)-6 stereoisomer. The phenylethylamino group appears to play a key role on the activity, but introduction of groups of different sizes and electronegativity does not induce a substantial change in affinity for the A2AAR. In functional assays, most of the compounds produced similar amounts of cAMP compared to NECA, thus behaving as full A2AAR agonists. In addition, compounds 1, 2, 3, 5,(S)-6 and 9 resulted to be good antagonists for A3AR with KB in the 6–14 nM range. Docking studies on the A2AAR showed a conserved binding mode consistent with previous A2AAR agonist-bound crystal structures, allowing for a rational interpretation of the SAR of this compound series.Adenosine is a ubiquitous purine nucleoside that mediates a range of physiological processes, such as those related to the cardiovascular system, kidney, CNS, cancer, inflammation, etc. through activation of the adenosine receptors (ARs). 1–5 Four ARs exist, namely A1, A2A, A2B and A3, all belonging to the class A (rhodopsin-like) family of G-protein coupled receptors (GPCRs). 6 All four ARs regulate the activity of adenylyl cyclase, stimulating (A2A and A2B, coupled to Gs) or …