In a previous paper (Colotta V. et al., J. Med. Chem. 2000, 43, 1158), we reported the synthesis and the binding activity of some 4-oxo (A) and 4-amino (B) substituted 1,2,4-triazolo[4,3-a]quinoxalin-1-ones, bearing different substituents on the appended 2-phenyl ring (region 1), some of which were potent and selective A(1) or A(3) antagonists. To further investigate the SAR in this class of antagonists, in the present paper some 2-phenyl-1,2,4-triazolo[4,3-a]quinoxalin-1-one derivatives of both series A and B, bearing simple substituents on the benzofused moiety (region 2), are reported. The binding data at bovine A(1) (bA(1)) and A(2A)(bA(2A)) and at human A(3) (hA(3)) adenosine receptors (ARs) show that in series A (compounds 1, 4-11) the presence of substituents on the benzofused moiety is, in general, not advantageous for anchoring at all three AR subtypes, while within series B (compounds 12-21) it exerts a beneficial effect for both bA(1) and hA(3) AR affinities which span the low nanomolar range. In particular, among the 4-amino derivatives 12-21, the 8-chloro-6-nitro (compound 17) and the 6-nitro (compound 18) substitutions afford, respectively, the highest bA(1) and hA(3) AR affinity. Moreover, compound 18, additionally investigated in binding assays at human A(1) (hA(1)) receptors, shows a 183-fold selectivity for hA(3) versus hA(1) receptors. Finally, the SAR studies provide some new insights about the steric and lipophilic requirements of the hA(3) receptor binding pocket which accommodates the benzofused moiety of our 4-amino-triazoloquinoxalin-1-one derivatives. (C) 2003 Elsevier Ltd. All rights reserved.
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