Structure–Activity Relationship Analysis of 2‑Aryl-8-alkynyl Adenine and Nucleoside Scaffolds as A3 Adenosine Receptor Ligands

Numerous adenosine receptor (AR) ligands have been synthesized over many years, but the development of 2,8-disubstituted nucleoside derivatives was limited due to the lack of efficient synthetic methods. Leveraging Pd catalyst-controlled regioselective coupling, we embarked on structure–activity relationship (SAR) analyses at the C8 position. Our SAR studies revealed that an aliphatic alkyne chain of specific length, such as 1-hexyne, at the C8 position is ideally suited for hA2AAR interaction. A computational docking study revealed that the π–π interaction between His953.37 and C8-aromatic alkyne could induce an active conformation of hA3AR. Notably, compound 7b demonstrated exceptional potency and selectivity at hA3AR (Ki,hA3 = 3.0 ± 0.5 nM), acting as the first 2,8-disubstituted nucleoside A3AR partial agonist. It underscores the strategic importance of C8 position modifications in modulating AR activity and function, paving the way for novel therapeutic agents targeting AR-mediated diseases.