N‑Substituted Phenoxazine and Acridone Derivatives: Structure–Activity Relationships of Potent P2X4 Receptor Antagonists

P2X4 receptor antagonists have potential as drugs for the treatment of neuropathic pain and neurodegenerative diseases. In the present study the discovery of phenoxazine derivatives as potent P2X4 antagonists is described. N-Substituted phenoxazine and related acridone and benzoxazine derivatives we...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2012-11, Vol.55 (22), p.9576-9588
Main Authors: Hernandez-Olmos, Victor, Abdelrahman, Aliaa, El-Tayeb, Ali, Freudendahl, Diana, Weinhausen, Stephanie, Müller, Christa E
Format: Article
Language:English
Subjects:
Acridines - chemistry
Acridones
Adenosine Triphosphate - metabolism
Animals
Astrocytoma - drug therapy
Astrocytoma - metabolism
Brain Neoplasms - drug therapy
Brain Neoplasms - metabolism
Calcium - metabolism
Cells, Cultured
CHO Cells
Cricetinae
Humans
Mice
Molecular Structure
Oxazines - chemistry
Oxazines - pharmacology
Purinergic P2 Receptor Antagonists - chemistry
Purinergic P2 Receptor Antagonists - pharmacology
Radioligand Assay
Rats
Receptors, Purinergic P2X4 - chemistry
Receptors, Purinergic P2X4 - metabolism
Species Specificity
Structure-Activity Relationship
Sulfonamides - chemistry
Sulfonamides - pharmacology
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Summary:P2X4 receptor antagonists have potential as drugs for the treatment of neuropathic pain and neurodegenerative diseases. In the present study the discovery of phenoxazine derivatives as potent P2X4 antagonists is described. N-Substituted phenoxazine and related acridone and benzoxazine derivatives were synthesized and optimized with regard to their potency to inhibit ATP-induced calcium influx in 1321N1 astrocytoma cells stably transfected with the human P2X4 receptor. In addition, species selectivity (rat, mouse, human) and receptor subtype selectivity (versus P2X1,2,3,7) were investigated. The most potent P2X4 antagonist of the present series was N-(benzyloxycarbonyl)phenoxazine (26, PSB-12054) with an IC50 of 0.189 μM and good selectivity versus the other human P2X receptor subtypes. N-(p-Methylphenylsulfonyl)phenoxazine (21, PSB-12062) was identified as a selective P2X4 antagonist that was equally potent in all three species (IC50: 0.928–1.76 μM). The compounds showed an allosteric mechanism of action. The present study represents the first structure–activity relationship analysis of P2X4 antagonists.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm300845v