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Recent research exploring C8 substitution on the caffeine core identified 8-(2-phenylethyl)-1,3,7-trimethylxanthine as a non-selective adenosine receptor antagonist. To elaborate further, we included various C8 two-chain-length linkers to enhance adenosine receptor affinity. The results indicated that the unsubstituted benzyloxy linker ( 1e A 1 K i = 1.52 μM) displayed the highest affinity for the A 1 adenosine receptor and the para -chloro-substituted phenoxymethyl ( 1d A 2A K i = 1.33 μM) linker the best A 2A adenosine receptor affinity. The position of the oxygen revealed that the phenoxymethyl linker favoured A 1 adenosine receptor selectivity over the benzyloxy linker and, by introducing a para -chloro substituent, A 2A adenosine receptor selectivity was obtained. Selected compounds ( 1c , 1e ) behaved as A 1 adenosine receptor antagonists in GTP shift assays and therefore represent selective and non-selective A 1 and A 2A adenosine receptor antagonists that may have potential for treating neurological disorders. [ABSTRACT FROM AUTHOR]