1 research outputs found
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 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 <i>N</i>-(benzyloxycarbonyl)Âphenoxazine
(<b>26</b>, PSB-12054) with an IC<sub>50</sub> of 0.189 μM
and good selectivity versus the other human P2X receptor subtypes. <i>N</i>-(<i>p</i>-Methylphenylsulfonyl)Âphenoxazine (<b>21</b>, PSB-12062) was identified as a selective P2X4 antagonist
that was equally potent in all three species (IC<sub>50</sub>: 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