title: Synthesis, ligand-receptor modeling studies and pharmacological evaluation of novel 4-modified-2-aryl-1,2,4-triazolo[4,3-a]quinoxalin-1-one derivatives as potent and selective human A3 adenosine receptor antagonists.
abstract: The study of some 4-substituted-2-aryl-1,2,4-triazolo[4,3-a]quinoxalin-1-one derivatives, designed as hA(3) adenosine receptor antagonists, is reported. The new compounds bear on the four-position different acylamino, sulfonylamino, benzylureido and benzyloxy moieties, which have also been combined with a para-methoxy group on the 2-phenyl ring or with a nitro residue at the six-position. Many derivatives show high hA(3) adenosine receptor affinities and selectivities both versus hA(1) and hA(2A) receptors. The observed structure-affinity relationships of this class of antagonists have been exhaustively rationalized using the recently published ligand-based homology modeling (LBHM) approach. The selected 4-bismethanesulfonylamino-2-phenyl-1,2,4-triazolo[4,3-a]quinoxalin-1-one (13), which shows high hA(3) affinity (K(i)=5.5nM) and selectivity versus hA(1), hA(2A) (both selectivity ratios>1800) and hA(2B) (cAMP assay, IC(50)>10,000nM) receptors, was tested in an in vitro rat model of cerebral ischemia, proving to be effective in preventing the failure of synaptic activity, induced by oxygen and glucose deprivation in the hippocampus, and in delaying the occurrence of anoxic depolarization.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Laboratorio di Progettazione, Sintesi e Studio di Eterocicli Biologicamente Attivi, Universita' di Firenze, Polo Scientifico, Via Ugo Schiff, 6, 50019 Sesto Fiorentino, FI, Italy. vittoria.colotta@unifi.it
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: Ombretta
authors.initials: O
authors.lastname: Lenzi
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: Chiara
authors.initials: C
authors.lastname: Traini
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Pugliese
authors.forename: Felicita
authors.initials: F
authors.lastname: Pedata
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; D002545:Brain Ischemia / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D002417:Cattle; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D043684:Receptor, Adenosine A3 / Q000378:metabolism / Q000502:physiology; D012243:Rhodopsin / Q000737:chemistry; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D014970:Xanthines / Q000378:metabolism / Q000494:pharmacology
chemical_list: C469661:1,2,4-triazolo(4,3-a)quinoxaline; D058918:Adenosine A3 Receptor Antagonists; D008024:Ligands; D011810:Quinoxalines; D043684:Receptor, Adenosine A3; D014230:Triazoles; D014970:Xanthines; D012243:Rhodopsin; C051360:1,3-dipropyl-8-cyclopentylxanthine