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.
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.
Colotta
Vittoria
V
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
Lenzi
Ombretta
O
Catarzi
Daniela
D
Varano
Flavia
F
Filacchioni
Guido
G
Martini
Claudia
C
Trincavelli
Letizia
L
Ciampi
Osele
O
Pugliese
Anna Maria
AM
Traini
Chiara
C
Pedata
Felicita
F
Morizzo
Erika
E
Moro
Stefano
S
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
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