title: 2-aryl-8-chloro-1,2,4-triazolo[1,5-a]quinoxalin-4-amines as highly potent A1 and A3 adenosine receptor antagonists.
abstract: Some 2-aryl-8-chloro-1,2,4-triazolo[1,5-a]quinoxaline derivatives 2-18, obtained by introducing different substituents on either the 4-amino moiety (acyl or carbamoyl groups) or the 2-phenyl ring (4-OCH3) of previously reported 8-chloro-2-phenyl-1,2,4-triazolo[1,5-a]quinoxalin-4-amine (1), have been synthesized and tested in radioligand binding assays at bovine A1 and A(2A) and at cloned human A1 and A3 adenosine receptors. The rationally designed 8-chloro-2-(4-methoxy-phenyl)-1,2,4-triazolo[1,5-a]quinoxalin-4-acetylamine (14) can be considered one of the most potent and hA3 versus hA1 selective AR antagonists reported till now. The structure-activity relationships of compounds 2-18 are in agreement with those of previously reported 2-aryl-1,2,4-triazolo[4,3-a]quinoxalines (series A) and 2-arylpyrazolo[3,4-c]quinolines (series B), thus suggesting a similar AR binding mode. In fact, the importance for the A3 receptor-ligand interaction of both a strong acidic NH proton donor and a C=O proton acceptor at position-4, able to engage hydrogen-bonding interactions with specific sites on the A3 AR, has been confirmed. Using our recently published hA3 receptor model, to better elucidate our experimental results, we decided to theoretically depict the putative TM binding motif of the herein reported 1,2,4-triazolo[1,5-a]quinoxaline derivatives on human A3 receptor. Structure-activity relationships have been explained analyzing the three-dimensional structure of the antagonist-receptor models obtained by molecular docking simulation.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Firenze, Polo Scientifico, Via U. Schiff, 6, 50019 Sesto Fiorentino (Firenze), Italy. daniela.catarzi@unifi.it
authors.forename: Daniela
authors.initials: D
authors.lastname: Catarzi
authors.forename: Vittoria
authors.initials: V
authors.lastname: Colotta
authors.forename: Flavia
authors.initials: F
authors.lastname: Varano
authors.forename: Francesca Romana
authors.initials: FR
authors.lastname: Calabri
authors.forename: Ombretta
authors.initials: O
authors.lastname: Lenzi
authors.forename: Guido
authors.initials: G
authors.lastname: Filacchioni
authors.forename: Letizia
authors.initials: L
authors.lastname: Trincavelli
authors.forename: Claudia
authors.initials: C
authors.lastname: Martini
authors.forename: Andrea
authors.initials: A
authors.lastname: Tralli
authors.forename: Christian
authors.initials: C
authors.lastname: Montopoli
authors.forename: Stefano
authors.initials: S
authors.lastname: Moro
mesh_terms: D000818:Animals; D002417:Cattle; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D058915:Purinergic P1 Receptor Antagonists; D011810:Quinoxalines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D058915:Purinergic P1 Receptor Antagonists; D011810:Quinoxalines