title: Pyrido[2,3-e]-1,2,4-triazolo[4,3-a]pyrazin-1-one as a new scaffold to develop potent and selective human A3 adenosine receptor antagonists. Synthesis, pharmacological evaluation, and ligand-receptor modeling studies.
abstract: The paper describes a new class of human (h) A(3) adenosine receptor antagonists, the 2-arylpyrido[2,3-e]-1,2,4-triazolo[4,3-a]pyrazin-1-one derivatives (PTP), either 4-oxo (1-6, series A) or 4-amino-substituted (7-20, series B). In both series A and B, substituents able to act as hydrogen bond acceptors (OMe, OH, F, COOEt) were inserted on the 2-phenyl ring. In series B, cycloalkyl and acyl residues were introduced on the 4-amino group. Some of the new derivatives showed high hA(3) AR affinities (K(i) < 50 nM) and selectivities vs both hA(1) and hA(2A) receptors. The selected 4-benzoylamino-2-(4-methoxyphenyl)pyrido[2,3-e]-1,2,4-triazolo[4,3-a]pyrazin-1-one (18), tested in an in vitro rat model of cerebral ischemia, proved to be effective in preventing the failure of synaptic activity induced by oxygen and glucose deprivation in the hippocampus. Molecular docking of this new class of hA(3) AR antagonists was carried out to depict their hypothetical binding mode to our refined model of hA(3) receptor.
authors.affiliation: Laboratorio di Progettazione, Sintesi e Studio di Eterocicli Biologicamente Attivi, Dipartimento di Scienze Farmaceutiche, Universita di Firenze, Polo Scientifico, Via Ugo Schiff, 6, 50019 Sesto Fiorentino, Italy. vittoria.colotta@unifi.it
authors.forename: Vittoria
authors.initials: V
authors.lastname: Colotta
authors.forename: Ombretta
authors.initials: O
authors.lastname: Lenzi
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: Anna Maria
authors.initials: AM
authors.lastname: Pugliese
authors.forename: Chiara
authors.initials: C
authors.lastname: Traini
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; D002545:Brain Ischemia / Q000503:physiopathology / Q000517:prevention & control; D002417:Cattle; D002460:Cell Line; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D009435:Synaptic Transmission / Q000187:drug effects; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C540337:4-benzoylamino-2-(4-methoxyphenyl)pyrido(2,3-e)-1,2,4-triazolo(4,3-a)pyrazin-1-one; D058918:Adenosine A3 Receptor Antagonists; D006575:Heterocyclic Compounds, 3-Ring; D008024:Ligands; D011719:Pyrazines; D011725:Pyridines; D014230:Triazoles; D000242:Cyclic AMP