4'-Thionucleosides as adenosine A₃ receptor ligands: a medicinal chemistry perspective

The adenosine A₃ receptor (A₃AR) is recognized as a potential therapeutic target across multiple human pathologies; however, the development of selective orthosteric ligands remains challenging due to receptor subtype conservation and species-dependent pharmacology. Among nucleoside-derived chemotypes, 4'-thionucleosides, generated by bioisosteric replacement of the ribose endocyclic oxygen with sulfur, constitute a synthetically accessible scaffold for modulating A₃AR activity. This review summarizes synthetic methodologies that have enabled systematic diversification of the 4'-thio chemotype, including β-selective N-glycosylation and de novo cyclization strategies, and analyzes structure-activity relationships (SAR) associated with modifications at the N⁶, C2, and 5' positions, as well as ribose truncation. These structural variations have been correlated with changes in binding affinity, subtype selectivity, and intrinsic efficacy, supporting the utility of the 4'-thio scaffold in generating distinct pharmacological profiles. The recent availability of cryo-electron microscopy structures of human A₃AR, including active agonist-bound states and, more recently, an inactive antagonist-bound conformation, provides a structural context for interpretation of established SAR trends and may facilitate future structure-guided and modeling-informed ligand optimization.