Abstract
The synthesis of epibatidine derivatives modified at the 2-position of the pyridine or pyrimidine rings by reactive functions are described for potential irreversible site-directed coupling reactions on cysteine mutants of neuronal nicotinic acetylcholine receptors. An improved synthesis of the 7-azabicyclo[2,2,1]hepta-2,5-diene key intermediate has been developed to allow reproducible syntheses of the epibatidine derivatives. Binding tests and electrophysiological experiments allowed to select the 2-substituted alpha-chloroacetamido 13 and the chloropyrimidine derivative 11 as potential site-directed probes for the epibatidine binding site.
MeSH terms
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Animals
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Brain Chemistry / drug effects
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Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis
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Bridged Bicyclo Compounds, Heterocyclic / chemistry
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
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Cell Line
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Cysteine / chemistry*
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Membrane Potentials / drug effects
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Mutagenesis, Site-Directed
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Mutation / genetics
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Neurons / drug effects
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Neurons / metabolism
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Nicotinic Agonists / chemical synthesis
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Nicotinic Agonists / chemistry
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Nicotinic Agonists / pharmacology*
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Pyridines / chemical synthesis
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Pyridines / chemistry
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Pyridines / pharmacology*
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Pyrimidines / chemistry
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Pyrimidines / pharmacology
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Rats
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Receptors, Nicotinic / drug effects
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Recombinant Fusion Proteins / metabolism
Substances
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Bridged Bicyclo Compounds, Heterocyclic
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Nicotinic Agonists
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Pyridines
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Pyrimidines
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Receptors, Nicotinic
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Recombinant Fusion Proteins
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Cysteine
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epibatidine