Abstract
N'-aryl acyl hydrazides were identified as P2X7 receptor antagonists. Structure-activity relationship (SAR) studies evaluated functional activity by monitoring calcium flux inhibition in cell lines expressing recombinant human and rat P2X7 receptors. Selected analogs were assayed in vitro for their capacity to inhibit release of cytokine IL-1beta. Compounds with potent antagonist function were evaluated in vivo using the zymosan-induced peritonitis model. A representative compound effectively attenuated mechanical allodynia in a rat model of neuropathic pain.
MeSH terms
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Analgesics / chemical synthesis*
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Analgesics / chemistry
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Analgesics / pharmacology
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Animals
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Calcium / metabolism
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Cell Line
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Humans
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Hydrazines / chemical synthesis*
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Hydrazines / chemistry
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Hydrazines / pharmacology
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Interleukin-1beta / antagonists & inhibitors
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Interleukin-1beta / metabolism
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Isoquinolines / chemical synthesis
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Isoquinolines / chemistry
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Isoquinolines / pharmacology
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Pain / drug therapy
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Pain Measurement
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Peripheral Nervous System Diseases / drug therapy
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Peritoneal Cavity
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Peritonitis / metabolism
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Peritonitis / prevention & control
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Purinergic P2 Receptor Antagonists*
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Quinolines / chemical synthesis
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Quinolines / chemistry
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Quinolines / pharmacology
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Rats
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Receptors, Purinergic P2X7
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Recombinant Proteins / antagonists & inhibitors
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Structure-Activity Relationship
Substances
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Analgesics
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Hydrazines
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Interleukin-1beta
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Isoquinolines
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P2RX7 protein, human
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P2rx7 protein, rat
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Purinergic P2 Receptor Antagonists
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Quinolines
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Receptors, Purinergic P2X7
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Recombinant Proteins
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Calcium