Abstract
All four stereoisomers of (+/-)-2-(methoxycarbonyl)-7-methyl-3-phenyl-7-azabicyclo[2.2. 1]heptane were synthesized and evaluated as cocaine binding site ligands at the dopamine transporter. The in vitro binding affinities (Ki) of the 7-azabicyclo[2.2.1]heptane derivatives were measured in rat caudate-putamen tissue and found to be 100-3000-fold less potent (Ki = 5-96 microM) than cocaine and 2beta-(methoxycarbonyl)-3beta-phenyltropane (2, WIN 35,065-2). Surprisingly, the 3alpha-phenyl isomers (6c, 6d) were more potent than the 3beta-phenyl isomers (6a, 6b). Molecular modeling studies revealed that the rigid 7-azabicyclo[2.2.1]heptane derivatives possess molecular topologies which are significantly different than the molecular topologies of the 2beta-(methoxycarbonyl)-3-phenyltropanes.
Publication types
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Comparative Study
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Binding, Competitive
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Carrier Proteins / metabolism*
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Caudate Nucleus / metabolism
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Cocaine / analogs & derivatives
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Cocaine / metabolism
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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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Models, Molecular
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Molecular Conformation
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Nerve Tissue Proteins*
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Protein Binding
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Putamen / metabolism
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Rats
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Stereoisomerism
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Tropanes / chemical synthesis*
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Tropanes / chemistry
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Tropanes / metabolism*
Substances
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2-(methoxycarbonyl)-7-methyl-3-phenyl-7-azabicyclo(2.1.1)heptane
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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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Tropanes
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(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester
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Cocaine