A comparison of adenosine receptor binding affinities of substituted xanthine derivatives with adenosine derivatives bearing the same substituents has led to the suggestion that different binding modes are operative for these two classes of adenosine receptor agents. In this communication we provide corroboration for this suggestion and propose a specific new binding mode for xanthines with respect to adenosines. This new binding mode is supported with partial atomic charge comparisons, molecular modeling, and a novel synthesis of xanthines that allows the introduction of chiral recognition units at the 8-position.