Discovery of a Novel Template, N 3‑1'-Homologated 4'-Truncated Thiosugar-Substituted Xanthine as an A3AR Antagonist via Conversion of an A1AR Antagonist

Adenosine receptors (ARs) are G protein-coupled receptors involved in diverse physiological and pathological processes. Among them, the A₃ subtype (A₃AR) is an attractive therapeutic target due to its low basal expression and strong upregulation in inflamed or tumor tissues. Here, an A₁AR-derived xanthine scaffold was repurposed toward A₃AR 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 A₃AR binding (K _i = 6.8 nM) with functional antagonism, showing an enhanced A₁/A₃ selectivity index (72) compared with that of the known xanthine-based A₃AR antagonist I-ABOPX (4.5). These findings demonstrate that thiosugar homologation effectively redirects xanthine scaffolds toward selective A₃AR antagonists and identify 5p as a promising lead compound.

Adenosine receptors; Antagonist; Structure−activity relationship (SAR); Thiosugar conjugation; Xanthine.