title: 4-amido-2-aryl-1,2,4-triazolo[4,3-a]quinoxalin-1-ones as new potent and selective human A3 adenosine receptor antagonists. synthesis, pharmacological evaluation, and ligand-receptor modeling studies.
abstract: A structural investigation on some 4-amido-2-phenyl-1,2-dihydro-1,2,4-triazolo[4,3-a]quinoxalin-1-one derivatives, designed as human A3 adenosine receptor (hA3 AR) antagonists, is described. In the new derivatives, some acyl residues with different steric bulk were introduced on the 4-amino group, and their combination with the 4-methoxy group on the 2-phenyl moiety, and/or the 6-nitro/6-amino substituent on the fused benzo ring, was also evaluated. Most of the new derivatives were potent and selective hA3 AR antagonists. SAR analysis showed that hindering and lipophilic acyl moieties not only are well tolerated but even ameliorate the hA3 affinity. Interestingly, the 4-methoxy substituent on the appended 2-phenyl moiety, as well as the 6-amino group, always exerted a positive effect, shifting the affinity toward the hA3 receptor subtype. In contrast, the 6-nitro substituent exerted a variable effect. An intensive molecular modeling investigation was performed to rationalize the experimental SAR findings.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Laboratorio di Progettazione, Sintesi e Studio di Eterocicli Biologicamente Attivi, Università di Firenze, Polo Scientifico, Via Ugo Schiff, 6, 50019 Sesto Fiorentino, Italy.
authors.forename: Ombretta
authors.initials: O
authors.lastname: Lenzi
authors.forename: Vittoria
authors.initials: V
authors.lastname: Colotta
authors.forename: Daniela
authors.initials: D
authors.lastname: Catarzi
authors.forename: Flavia
authors.initials: F
authors.lastname: Varano
authors.forename: Guido
authors.initials: G
authors.lastname: Filacchioni
authors.forename: Claudia
authors.initials: C
authors.lastname: Martini
authors.forename: Letizia
authors.initials: L
authors.lastname: Trincavelli
authors.forename: Osele
authors.initials: O
authors.lastname: Ciampi
authors.forename: Katia
authors.initials: K
authors.lastname: Varani
authors.forename: Federico
authors.initials: F
authors.lastname: Marighetti
authors.forename: Erika
authors.initials: E
authors.lastname: Morizzo
authors.forename: Stefano
authors.initials: S
authors.lastname: Moro
mesh_terms: D058918:Adenosine A3 Receptor Antagonists; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D002417:Cattle; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D008566:Membranes; D008958:Models, Molecular; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D058918:Adenosine A3 Receptor Antagonists; D008024:Ligands; D011810:Quinoxalines; D014230:Triazoles; D000242:Cyclic AMP