1,2,4-Triazolo[4,3-a]quinoxalin-1-one: A Versatile Tool for the Synthesis of Potent and Selective Adenosine Receptor Antagonists

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Abstract
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 A2A versus A1 selective antagonist (Colotta et al. Arch. Pharm. Pharm. Med. Chem. 1999, 332, 39−41). In this paper 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-phenyl-1,2,4-triazolo[4,3-a]quinoxalin-1-one (3) have been synthesized and tested in radioligand binding assays at bovine A1 and A2A and cloned human A3 adenosine receptors (AR). Moreover, the binding activities at the above-mentioned AR subtypes of the 1,4-dione parent compounds 26 − 31 and their 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 of a hydrogen atom of the 4-amino group with suitable substituents yielded selective A1 or A3 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 moiety, shifted the binding activity toward the A3 AR. The binding results allowed elucidation of the structural requirements for the binding of these novel tricyclic derivatives at each receptor subtype. In particular, A1 and A2A binding required the presence of a proton donor group at position-4, while for A3 affinity the presence of a proton acceptor in this same region was of paramount importance.