Mol. modeling studies, including the comparative mol. field anal. (CoMFA) method, on 52 antagonists of the A2B adenosine receptor with known biol. activity were performed to identify the three-dimensional features responsible for A2B adenosine receptor antagonist activity. On the basis of these and previous results on the potent antagonist effect of 8-pyrazolyl-xanthines at human A2BAR, a new series of compds. was synthesized and evaluated in binding studies against the human A1, A2A, A3, and A2BARs. A remarkable improvement in selectivity with respect to the previous series, maintaining the potency at human A2B receptor, was achieved, as exemplified by the 8-[3-(4-chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl-methoxy)-1-methyl-1H-pyrazol-5-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (I): Ki A2B = 9.4 nM, IC50 hA2B = 26 nM hA1/hA2B = 269, hA2A/hA2B > 106, hA3/hA2B >106. This study also led to the identification of a series of pyrazole-xanthine compds. with a simplified structure, exemplified by 8-(3-hydroxy-1-methyl-1H-pyrazol-5-yl)-xanthine (II) displaying very high affinity at A2BAR with good selectivity over AR subtypes (Ki = 4.0 nM, IC50 hA2B = 20 nM hA1/hA2B = 183, hA2A,hA3/hA2B > 250).