1,2,4-Triazolo[4,3-a]quinoxalin-1-one: a versatile tool for the synthesis of 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 (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 A(1) and A(2A) and cloned human A(3) 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 A(1) or A(3) antagonists. Replacement of a hydrogen atom of the 4-NH(2) with an acyl group, or replacement of the whole 4-NH(2) with a 4-oxo moiety, shifted the binding activity toward the A(3) AR. The binding results allowed elucidation of the structural requirements for the binding of these novel tricyclic derivatives at each receptor subtype. In particular, A(1) and 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 region was of paramount importance.
Colotta
V
V
Dipartimento di Scienze Farmaceutiche, Universita' di Firenze, Via G. Capponi, 9, 50121 Firenze, Italy.
Catarzi
D
D
Varano
F
F
Cecchi
L
L
Filacchioni
G
G
Martini
C
C
Trincavelli
L
L
Lucacchini
A
A
D000818:Animals; D001667:Binding, Competitive; D002417:Cattle; D002460:Cell Line; D002540:Cerebral Cortex / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D058915:Purinergic P1 Receptor Antagonists; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011869:Radioligand Assay; D043705:Receptor, Adenosine A2A; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D013329:Structure-Activity Relationship
D058915:Purinergic P1 Receptor Antagonists; D011810:Quinoxalines; D043705:Receptor, Adenosine A2A; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1