Abstract
A series of 9-methyl-3 beta-phenyl-2-substituted-9-azabicyclo[3.3.1]nonane derivatives were synthesized and evaluated as cocaine-binding site ligands at the dopamine transporter (DAT). The conformation of the bicyclic structures and the stereochemistry of the substituents were determined by NMR and X-ray crystallography. The in vitro binding affinity (Ki) of the 9-azabicyclo[3.3.1]nonane derivatives was measured in rat caudate-putamen tissue, and they were found to be 100-fold (Ki = 2-14 microM) less potent than cocaine and other tropane analogs. From these results it is evident that the cocaine-binding site at the DAT is very sensitive to structural modifications of the unsubstituted methylene bridge [C(6)-C(7)] of cocaine and cocaine-like compounds.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Aza Compounds / chemical synthesis
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Aza Compounds / pharmacology*
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Binding Sites
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Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
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Bridged Bicyclo Compounds, Heterocyclic / metabolism
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Carrier Proteins / antagonists & inhibitors
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Carrier Proteins / metabolism*
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Cocaine / pharmacology
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Crystallography, X-Ray
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Dopamine Plasma Membrane Transport Proteins
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Magnetic Resonance Spectroscopy
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Membrane Glycoproteins*
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Membrane Transport Proteins*
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Molecular Conformation
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Molecular Structure
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Nerve Tissue Proteins*
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Protein Binding
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Rats
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Receptors, Drug / metabolism
Substances
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Aza Compounds
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Bridged Bicyclo Compounds, Heterocyclic
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Carrier Proteins
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Dopamine Plasma Membrane Transport Proteins
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Membrane Glycoproteins
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Membrane Transport Proteins
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Nerve Tissue Proteins
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Receptors, Drug
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Slc6a3 protein, rat
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cocaine receptor
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Cocaine