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

The characterization of the native and recombinant P2X7 receptor continues to be hindered by the lack of specific and subtype-selective antagonists with a “druglike” profile. However, a tyrosine derivative named KN-62 exhibits selective P2X7 receptor-blocking properties. As a molecular simplificatio...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2007-07, Vol.50 (15), p.3706-3715
Main Authors: Romagnoli, Romeo, Baraldi, Pier Giovanni, Carrion, Maria Dora, Cara, Carlota Lopez, Preti, Delia, Cruz-Lopez, Olga, Tabrizi, Mojgan Aghazadeh, Moorman, Allan R, Gessi, Stefania, Fogli, Eleonora, Sacchetto, Valeria, Borea, Pier Andrea
Format: Article
Language:English
Subjects:
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - analogs & derivatives
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - chemistry
Adenosine Triphosphate - metabolism
beta-Alanine - analogs & derivatives
beta-Alanine - chemical synthesis
beta-Alanine - pharmacology
Biological and medical sciences
Calcium - metabolism
Cell Line
Cell Membrane - metabolism
Cell Membrane Permeability
Ethidium - metabolism
Fluorescent Dyes - metabolism
Glycine - analogs & derivatives
Glycine - chemical synthesis
Glycine - pharmacology
Humans
Isoquinolines - chemical synthesis
Isoquinolines - pharmacology
Medical sciences
Naphthalenes - chemical synthesis
Naphthalenes - pharmacology
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems
Pharmacology. Drug treatments
Purinergic P2 Receptor Antagonists
Receptors, Purinergic P2X7
Recombinant Proteins - antagonists & inhibitors
Structure-Activity Relationship
Sulfonamides - chemical synthesis
Sulfonamides - pharmacology
Sulfones - chemical synthesis
Sulfones - pharmacology
Tyrosine - chemistry
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Summary:The characterization of the native and recombinant P2X7 receptor continues to be hindered by the lack of specific and subtype-selective antagonists with a “druglike” profile. However, a tyrosine derivative named KN-62 exhibits selective P2X7 receptor-blocking properties. As a molecular simplification of KN-62, the present study was designed to evaluate the functional antagonistic properties of a novel series of glycine derivatives characterized by the presence of different phenyl-substituted piperazine moieties. Antagonistic activity 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-fluorine substituent on the phenylpiperazine moiety and had an IC50 of 12.1 nM. The biological responses investigated were ATP-dependent Ca2+ influx across the plasma membrane and ethidium bromide uptake.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm070443e