Selected C8 two-chain linkers enhance the adenosine A₁/A_2A receptor affinity and selectivity of caffeine

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 A₁K_i = 1.52 μM) displayed the highest affinity for the A₁ adenosine receptor and the para-chloro-substituted phenoxymethyl (1d A_2AK_i = 1.33 μM) linker the best A_2A adenosine receptor affinity. The position of the oxygen revealed that the phenoxymethyl linker favoured A₁ 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 A₁ adenosine receptor antagonists in GTP shift assays and therefore represent selective and non-selective A₁ and A_2A adenosine receptor antagonists that may have potential for treating neurological disorders.