Adenosine receptors (ARs), members of the G protein–coupled receptor (GPCR) family, regulate neuromodulation, inflammation, and immune responses. Among the four subtypes (A₁, A_2A, A_2B, A₃), the A₃ adenosine receptor (A₃AR) is an attractive therapeutic target because it is low in most normal tissues but selectively elevated in tumors and chronic inflammatory sites, enabling targeted intervention with reduced systemic toxicity. To address the unmet need for A3AR antagonists, we repurposed the xanthine core of DPCPX, an A1AR-selective antagonist, and introduced at N3 a 1′-homologated, 4′-truncated thiosugar to capture adenosine-like recognition elements while biasing subtype selectivity toward A₃AR. The resulting compounds showed enhanced A₃AR binding, and the lead displayed potent, full antagonism in cAMP assays. These results demonstrate that strategic sugar conjugation on a xanthine scaffold can convert an A₁AR antagonist into an selective A₃AR antagonist and provide a practical template for developing anti-inflammatory and anticancer agents.