1,2,4-triazolo[4,3-a]quinoxalin-1-one moiety as an attractive scaffold to develop new potent and selective human A3 adenosine receptor antagonists: synthesis, pharmacological, and ligand-receptor modeling studies.
In the past few years much effort in our laboratory has been directed toward the study of adenosine receptor antagonists, and recently we focused our attention on 2-aryl-1,2,4-triazolo[4,3-a]quinoxaline-1,4-diones and 2-aryl-1,2,4-triazolo[4,3-a]quinoxalin-4-amino-1-ones, some of which were potent and/or selective A(3) receptor antagonists. In the present paper, a new series of triazoloquinoxaline derivatives is described. Most of the new compounds, biologically evaluated in radioligand binding assays at bovine (b) A(1) and A(2A) and at human (h) A(1) and A(3) adenosine receptors, showed high hA(3) adenosine receptor affinity and selectivity. In particular, 2-(4-nitrophenyl)-1,2,4,5-tetrahydro-1,2,4-triazolo[4,3-a]quinoxaline-1,4-dione (1), also tested at the hA(2A) ARs, shows the best binding profile with a high hA(3) affinity (K(i) = 0.60 nM) and strong selectivity vs hA(1) and vs hA(2A) receptors (both selectivity ratios greater than 16 600). To interpret our experimental results, we decided to theoretically depict the putative transmembrane binding motif of our triazoloquinoxaline analogues on hA(3) receptor. Structure-activity relationships have been explained analyzing the three-dimensional structure of the antagonist-receptor models obtained by molecular docking simulation.
Colotta
Vittoria
V
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Firenze, Polo Scientifico, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy. vittoria.colotta@unifi.it
Catarzi
Daniela
D
Varano
Flavia
F
Calabri
Francesca Romana
FR
Lenzi
Ombretta
O
Filacchioni
Guido
G
Martini
Claudia
C
Trincavelli
Letizia
L
Deflorian
Francesca
F
Moro
Stefano
S
D058918:Adenosine A3 Receptor Antagonists; D000818:Animals; D016466:CHO Cells; D002417:Cattle; D006224:Cricetinae; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D043684:Receptor, Adenosine A3 / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C488112:2-(4-nitrophenyl)-1,2,4,5-tetrahydro-1,2,4-triazolo(4,3-a)quinoxaline-1,4-dione; D058918:Adenosine A3 Receptor Antagonists; D008024:Ligands; D011810:Quinoxalines; D043684:Receptor, Adenosine A3; D014230:Triazoles