A library of 27 novel amide derivatives of annelated xanthines was designed and synthesized. The new compounds represent 1,3-dipropyl- and 1,3-dibutyl-pyrimido[2,1-<i>f</i>]purinedione-9-ethylphenoxy derivatives including a CH<sub>2</sub>CONH linker between the (CH<sub>2</sub>)<sub>2</sub>-amino group and the phenoxy moiety. A synthetic strategy to obtain the final products was developed involving solvent-free microwave irradiation. The new compounds were evaluated for their adenosine receptor (AR) affinities. The most potent derivatives contained a terminal tertiary amino function. Compounds with nanomolar AR affinities and at the same time high water-solubility were obtained (A<sub>1</sub> (<i>K</i><sub>i</sub> = 24-605 nM), A<sub>2A</sub> (<i>K</i><sub>i</sub> = 242-1250 nM), A<sub>2B</sub> (<i>K</i><sub>i</sub> = 66-911 nM) and A<sub>3</sub> (<i>K</i><sub>i</sub> = 155-1000 nM)). 2-(4-(2-(1,3-Dibutyl-2,4-dioxo-1,2,3,4,7,8-hexahydropyrimido[2,1-<i>f</i>]purin-9(6<i>H</i>)-yl)ethyl)phenoxy)-<i>N</i>-(3-(diethylamino)propyl)acetamide (<b>27</b>) and the corresponding <i>N</i>-(2-(pyrrolidin-1-yl)ethyl)acetamide (<b>36</b>) were found to be the most potent antagonists of the present series. While <b>27</b> showed CYP inhibition and moderate metabolic stability, <b>36</b> was found to possess suitable properties for <i>in vivo</i> applications. In an attempt to explain the affinity data for the synthesized compounds, molecular modeling and docking studies were performed using homology models of A<sub>1</sub> and A<sub>2A</sub> adenosine receptors. The potent compound <b>36</b> was used as an example for discussion of the possible ligand-protein interactions. Moreover, the compounds showed high water-solubility indicating that the approach of introducing a basic side chain was successful for the class of generally poorly soluble AR antagonists.