Abstract
A series of 6alpha- and 6beta-substituted benztropines were synthesized. A marked enantioselectivity was observed for the 6beta-methoxylated benztropines, the (1R)-isomers being more potent than the corresponding (1S) compounds. The racemic 6alpha-methoxy-3-(4',4' '-difluorodiphenylmethoxy)tropane (5 g) was the most potent compound. It has been found that modifications at the 6-position of benztropine might reduce the DAT binding affinity, maintaining otherwise a significant dopamine uptake inhibitory activity. A reinvestigation of the absolute configuration of 6beta-methoxytropinone proved the 6R configuration for the (+)-enantiomer.
MeSH terms
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Animals
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Benztropine / analogs & derivatives*
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Benztropine / chemical synthesis*
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Benztropine / pharmacology
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Binding, Competitive
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Corpus Striatum / drug effects
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Corpus Striatum / metabolism
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Dopamine / metabolism
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Dopamine Plasma Membrane Transport Proteins
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Dopamine Uptake Inhibitors / chemical synthesis*
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Dopamine Uptake Inhibitors / pharmacology
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In Vitro Techniques
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Membrane Glycoproteins / metabolism*
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Membrane Transport Proteins / metabolism*
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Molecular Conformation
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Nerve Endings / drug effects
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Nerve Endings / metabolism
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Nerve Tissue Proteins / metabolism*
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Putamen / drug effects
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Putamen / metabolism
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Radioligand Assay
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Rats
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Stereoisomerism
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Structure-Activity Relationship
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Tropanes / chemical synthesis*
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Tropanes / pharmacology
Substances
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6-methoxy-3-(4',4''-difluorodiphenylmethoxy)tropane
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Dopamine Plasma Membrane Transport Proteins
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Dopamine Uptake Inhibitors
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Membrane Glycoproteins
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Membrane Transport Proteins
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Nerve Tissue Proteins
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Slc6a3 protein, rat
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Tropanes
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Benztropine
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Dopamine