Abstract
Two distinct families of small molecules were discovered as novel alpha7 nicotinic acetylcholine receptor (nAChR) antagonists by pharmacophore-based virtual screening. These novel antagonists exhibited selectivity for the neuronal alpha7 subtype over other nAChRs and good brain penetration. Neuroprotection was demonstrated by representative compounds 7i and 8 in a mouse seizure-like behavior model induced by the nerve agent diisopropylfluorophosphate (DFP). These novel nAChR antagonists have potential use as antidote for organophosphorus nerve agent intoxication.
2010 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Brain / metabolism
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Computer Simulation
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Disease Models, Animal
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Humans
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Mice
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Molecular Conformation
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Nicotinic Antagonists / chemical synthesis
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Nicotinic Antagonists / chemistry*
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Nicotinic Antagonists / therapeutic use
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Protein Binding
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Rats
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Receptors, Nicotinic / chemistry*
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Receptors, Nicotinic / metabolism
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Seizures / drug therapy
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Structure-Activity Relationship
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alpha7 Nicotinic Acetylcholine Receptor
Substances
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Chrna7 protein, human
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Chrna7 protein, mouse
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Chrna7 protein, rat
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Nicotinic Antagonists
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Receptors, Nicotinic
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alpha7 Nicotinic Acetylcholine Receptor