An-Najah Staff

Abstract Molecular modeling studies, including the comparative molecular field analysis (CoMFA) method, on 52 antagonists of the A(2B) adenosine receptor with known biological activity were performed to identify the three-dimensional features responsible for A(2B) adenosine receptor antagonist activity. On the basis of these and previous results on the potent antagonist effect of 8-pyrazolyl-xanthines at human A(2B)AR, a new series of compounds was synthesized and evaluated in binding studies against the human A(1), A(2A), A(3), and A(2B)ARs. A remarkable improvement in selectivity with respect to the previous series, maintaining the potency at human A(2B) 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 derivative 66: K(i) A(2B) = 9.4 nM, IC(50) hA(2B) = 26 nM hA(1)/hA(2B) = 269, hA(2A)/hA(2B) > 106, hA(3)/hA(2B) >106. This study also led to the identification of a series of pyrazole-xanthine compounds with a simplified structure, exemplified by 8-(3-hydroxy-1-methyl-1H-pyrazol-5-yl)-xanthine 80 displaying very high affinity at A(2B)AR with good selectivity over AR subtypes (K(i) = 4.0 nM, IC(50) hA(2B) = 20 nM hA(1)/hA(2B) = 183, hA(2A),hA(3)/hA(2B) > 250).