Abstract
Adenosine receptors (ARs) are G protein-coupled receptors involved in diverse physiological and pathological processes. Among them, the A(3) subtype (A(3)AR) is an attractive therapeutic target due to its low basal expression and strong upregulation in inflamed or tumor tissues. Here, an A(1)AR-derived xanthine scaffold was repurposed toward A(3)AR antagonism by introducing a 1'-homologated 4'-truncated thiosugar at the N3 position. Structure-activity studies identified C8 substitution as the key determinant of subtype selectivity, while N1 groups modulated binding cooperatively. The optimized analogue 5p exhibited potent and selective A(3)AR binding (K (i) = 6.8 nM) with functional antagonism, showing an enhanced A(1)/A(3) selectivity index (72) compared with that of the known xanthine-based A(3)AR antagonist I-ABOPX (4.5). These findings demonstrate that thiosugar homologation effectively redirects xanthine scaffolds toward selective A(3)AR antagonists and identify 5p as a promising lead compound.