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

被引：34

作者：

Colotta, Vittoria ^{[1
]}

Lenzi, Ombretta ^{[1
]}

Catarzi, Daniela ^{[1
]}

Varano, Flavia ^{[1
]}

Filacchioni, Guido ^{[1
]}

Martini, Claudia ^{[2
]}

Trincavelli, Letizia ^{[2
]}

Ciampi, Osele ^{[2
]}

Pugliese, Anna Maria ^{[3
]}

Traini, Chiara ^{[3
]}

Pedata, Felicita ^{[3
]}

Morizzo, Erika ^{[4
]}

Moro, Stefano ^{[4
]}

机构：

[1] Univ Florence, Dipartimento Sci Farmaceut, Lab Progettaz Sintesi & Studio Eterocicli Biologi, I-50019 Sesto Fiorentino, Italy

[2] Univ Pisa, Dipartimento Psichiat Neurobiol Farmacol & Biotec, I-56126 Pisa, Italy

[3] Univ Florence, Dipartimento Farmacol Preclin & Clin, I-50139 Florence, Italy

[4] Univ Padua, Dipartimento Sci Farmaceut, MMS, I-35131 Padua, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 08期

关键词：

GLUCOSE DEPRIVATION EPISODES; CRYSTAL-STRUCTURE; EXTRACELLULAR ADENOSINE; SPREADING DEPRESSION; VERSATILE TOOL; A(1); DERIVATIVES; BINDING; NEUROTRANSMISSION; HIPPOCAMPUS;

D O I：

10.1021/jm8014876

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：2407 / 2419

页数：13

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