Structure-Activity Relationship Analysis of 2-Aryl-8-alkynyl Adenine and Nucleoside Scaffolds as A 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 hAAR interaction. A computational docking study revealed that the π-π interaction between His95 and C8-aromatic alkyne could induce an active conformation of hAAR. Notably, compound demonstrated exceptional potency and selectivity at hAAR ( = 3.0 ± 0.5 nM), acting as the first 2,8-disubstituted nucleoside AAR 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.