Based on a previous report that a series of 8-(phenoxymethyl)-xanthines may be promising leads for the design of A1 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 A1 and A2A adenosine receptor affinity. Generally, the study compounds exhibited affinity for both the A1 and A2A adenosine receptors. Replacement of the 1,3-dimethyl-substition with a 1,3-diethyl-substition pattern increased A1 and A2A binding affinity. Overall it was found that para-substitution on the phenoxymethyl side-chain of the 1,3-diethyl-xanthines decreased A1 affinity except for the 4-Br analog (4f) exhibiting the best A1 affinity in the submicromolar range. On the other hand A2A affinity for the 1,3-diethyl-xanthines were increased with para-substitution and the 4-OCH3 (4b) analog showed the best A2A affinity with a Ki value of 237nM. The 1,3-diethyl-substituted analogs (4a, and 4f) behaved as A1 adenosine receptor antagonists in GTP shift assays performed with rat whole brain membranes expressing A1 adenosine receptors. This study concludes that para-substituted 1,3-diethyl-7-methyl-8-(phenoxymethyl)-xanthine analogs represent novel A1 and A2A adenosine receptor antagonists that are appropriate for the design of therapies for neurodegenerative disorders such as Parkinson's and Alzheimer's disease.