1,2,4-triazolol[4,3-a]quinoxalin-1-one: A versatile tool for the synthesisof potent and selective adenosine receptor antagonists

4-Amino-6-benzylamino-1,2-dihydro-2-phenyl-1,2,4-triazolo[4,3-a]quinoxalin- 1-one (1) has been found to be an A(2A) versus A(1) selective antagonist (C olotta et al. Arch. Pharm. Pharm. Med. Chem. 1999,332, 39-41). In this pape r some novel triazoloquinoxalin-1-ones 4-25 bearing different substituents on the 2-phenyl and/or 4-amino moiety of the parent 4-amino-1,2-dihydro-2-p henyl-1,2,4-triazolo[4,3-a]quinoxalin-1-one (3) have been synthesized and t ested in radioligand binding assays at bovine A(1) and A(2A) and cloned hum an A(3) adenosine receptors (AR). Moreover, the binding activities at the a bove-mentioned AR subtypes of the 1,4-dione parent compounds 26-31 and thei r 5-N-alkyl derivatives 33-37 were also evaluated. The substituent on the 2 -phenyl ring exerted a different effect on AR subtypes, while replacement o f a hydrogen atom of the 4-amino group with suitable substituents yielded s elective A(1) or A(3) antagonists. Replacement of a hydrogen atom of the 4- NH2 with an acyl group, or replacement of the whole 4-NH2 with a 4-oxo moie ty, shifted the binding activity toward the A(3) AR. The binding results al lowed elucidation of the structural requirements for the binding of these n ovel tricyclic derivatives at each receptor subtype. In particular, A(1) an d A(2A) binding required the presence of a proton donor group at position-4 , while for A(3) affinity the presence of a proton acceptor in this same re gion was of paramount importance.