Abstract
Rigidified derivatives have been designed and synthesized assuming the g+t conformer of acetylcholine (N-C-C-O=+60 degrees, C-C-O-C=180 degrees ) as active conformation for binding to cytisine sensitive neuronal nicotinic receptors. The SAR of the compounds evaluated, along with those of more flexible analogues, support the g+t conformer hypothesis and highlight the stringent steric limitation of this nicotinic receptor sub-type. Compound 3e has low microM affinity for cytisine sensitive nicotinic receptor binding sites while being selective with regard to the alpha-bungarotoxin sensitive subclass. We also report few compounds with microM affinity for the alpha-bungarotoxin sensitive subclass.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcholine / chemistry*
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Acetylcholine / metabolism
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Alkaloids / pharmacology
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Animals
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Azocines / pharmacology
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Bungarotoxins / pharmacology
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Drug Design
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Gas Chromatography-Mass Spectrometry
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In Vitro Techniques
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Indicators and Reagents
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Magnetic Resonance Spectroscopy
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Models, Molecular
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Molecular Conformation
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Molecular Mimicry
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Neurons / drug effects
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Neurons / metabolism*
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Prosencephalon / drug effects
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Prosencephalon / metabolism
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Quinolizines / pharmacology
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Radioligand Assay
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Rats
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Receptors, Nicotinic / drug effects*
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Structure-Activity Relationship
Substances
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Alkaloids
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Azocines
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Bungarotoxins
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Indicators and Reagents
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Quinolizines
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Receptors, Nicotinic
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cytisine
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Acetylcholine