Abstract
1-Benzyl-5-aryltetrazoles were discovered to be novel antagonists for the P2X(7) receptor. Structure-activity relationship (SAR) studies were conducted around both the benzyl and phenyl moieties. In addition, the importance of the regiochemical substitution on the tetrazole was examined. Compounds were evaluated for activity to inhibit calcium flux in both human and rat recombinant P2X(7) cell lines using fluorometric imaging plate reader technology. Analogues were also assayed for their ability to inhibit IL-1beta release and to inhibit P2X(7)-mediated pore formation in human THP-1 cells. Compound 15d was advanced to efficacy studies in a model of neuropathic pain where significant reversal of mechanical allodynia was observed at doses that did not affect motor coordination.
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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Cell Line
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Humans
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Interleukin-1 / antagonists & inhibitors
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Interleukin-1 / metabolism
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Ligation
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Motor Activity / drug effects
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Pain / drug therapy
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Pain / etiology
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Patch-Clamp Techniques
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Peripheral Nervous System Diseases / complications
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Physical Stimulation
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Purinergic P2 Receptor Antagonists*
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Pyridines / chemical synthesis*
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Pyridines / chemistry
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Pyridines / pharmacology
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Rats
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Receptors, Purinergic P2 / physiology
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Receptors, Purinergic P2X7
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Spinal Nerves
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Stereoisomerism
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Structure-Activity Relationship
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Tetrazoles / chemical synthesis*
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Tetrazoles / chemistry
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Tetrazoles / pharmacology
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Touch
Substances
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3-(5-(2,3-dichlorophenyl)tetrazol-1-ylmethyl)pyridine
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Analgesics
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Interleukin-1
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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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Pyridines
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Receptors, Purinergic P2
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Receptors, Purinergic P2X7
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Tetrazoles