From Tyrosine to Glycine: Synthesis and Biological Activity of Potent Antagonists of the Purinergic P2X7 Receptor

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• 作者：Romeo Romagnoli ; Pier Giovanni Baraldi ; Maria Dora Carrion ; Carlota Lopez Cara ; Delia Preti ; Olga Cruz-Lopez ; Mojgan Aghazadeh Tabrizi ; Allan R. Moorman ; Stefania Gessi ; Eleonora Fogli ; Valeria Sacche
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：July 26, 2007
• 年：2007
• 卷：50
• 期：15
• 页码：3706 - 3715
• 全文大小：145K
• 年卷期：v.50,no.15(July 26, 2007)
• ISSN：1520-4804

文摘

The characterization of the native and recombinant P2X₇ receptor continues to be hindered by the lack ofspecific and subtype-selective antagonists with a "druglike" profile. However, a tyrosine derivative namedKN-62 exhibits selective P2X₇ receptor-blocking properties. As a molecular simplification of KN-62, thepresent study was designed to evaluate the functional antagonistic properties of a novel series of glycinederivatives characterized by the presence of different phenyl-substituted piperazine moieties. Antagonisticactivity of these glycine derivatives was tested on HEK293 cells transfected with the human P2X₇ receptor.The most potent P2X₇ receptor antagonist identified in this study (compound 4g) contains an o-fluorinesubstituent on the phenylpiperazine moiety and had an IC₅₀ of 12.1 nM. The biological responses investigatedwere ATP-dependent Ca²⁺ influx across the plasma membrane and ethidium bromide uptake.