Discovery of 1,3-diethyl-7-methyl-8-(phenoxymethyl)-xanthine derivatives as novel adenosine A and A receptor antagonists.

Based on a previous report that a series of 8-(phenoxymethyl)-xanthines may be promising leads for the design of A adenosine receptor antagonists, selected novel and known 1,3-diethyl-7-methyl-8-(phenoxymethyl)-xanthine and 1,3,7-trimethyl-8-(phenoxymethyl)-xanthine analogs were synthesized and evaluated for their A and A adenosine receptor affinity. Generally, the study compounds exhibited affinity for both the A and A adenosine receptors. Replacement of the 1,3-dimethyl-substition with a 1,3-diethyl-substition pattern increased A and A binding affinity. Overall it was found that para-substitution on the phenoxymethyl side-chain of the 1,3-diethyl-xanthines decreased A affinity except for the 4-Br analog (4f) exhibiting the best A affinity in the submicromolar range. On the other hand A affinity for the 1,3-diethyl-xanthines were increased with para-substitution and the 4-OCH (4b) analog showed the best A affinity with a K value of 237nM. The 1,3-diethyl-substituted analogs (4a, and 4f) behaved as A adenosine receptor antagonists in GTP shift assays performed with rat whole brain membranes expressing A adenosine receptors. This study concludes that para-substituted 1,3-diethyl-7-methyl-8-(phenoxymethyl)-xanthine analogs represent novel A and A adenosine receptor antagonists that are appropriate for the design of therapies for neurodegenerative disorders such as Parkinson's and Alzheimer's disease.