Abstract
A series of cyclo-3beta-(4-aminophenyl)-2beta-tropanemethanol analogues (5a-m) possessing varying linker groups between the 2- and 3-position on the tropane ring were synthesized and evaluated for their monoamine transporter binding properties. The results show that binding to the dopamine and serotonin transporters (DAT and 5-HTT) is highly dependent on the specific linker used. Cyclo-3beta-(4-aminophenyl)-2beta-tropanemethanol pimelic acid ester/amide (5b) had an IC50 of 3.8 nM at the DAT. Cyclo-3beta-(4-aminophenyl)-2beta-tropanemethanol sebacic acid ester/amide (5e) had a Ki of 1.9 nM at the 5-HTT and was 68- and 737-fold selective for the 5-HTT relative to the DAT and NET. Small changes to the size as well as the electrostatic and hydrophobic properties of the 2,3-linker in 5b or 5e led to much less potent analogues at all three transporters. These results suggest that the high affinity for 5b and 5e at the DAT and 5-HTT may be due to their specific conformational properties.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Binding, Competitive
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Cocaine / analogs & derivatives*
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Cocaine / chemical synthesis
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Cocaine / chemistry
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Cocaine / pharmacology
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Crystallography, X-Ray
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Dopamine Plasma Membrane Transport Proteins / metabolism*
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Hydrophobic and Hydrophilic Interactions
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Models, Molecular
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Molecular Structure
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Norepinephrine Plasma Membrane Transport Proteins / metabolism*
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Radioligand Assay
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Rats
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Serotonin Plasma Membrane Transport Proteins / metabolism*
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Static Electricity
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Structure-Activity Relationship
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Tropanes / chemical synthesis*
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Tropanes / chemistry
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Tropanes / pharmacology
Substances
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4,5,6,7,8,9,10,11,13,17a,18,19,20,21,22,22a-hexadecahydro-23-methyl-14,17-etheno-19,22-imino-1H-cyclohept(c)(1,9)oxaazacyclononadecine-3,12-dione
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5,6,7,8,10,14a,15,16,17,18,19,19a-dodecahydro-20-methyl-11,14-etheno-16,19-iminocyclohept(c)(1,9)oxaazacyclohexadecine-3,9(1H,4H)-dione
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Dopamine Plasma Membrane Transport Proteins
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Norepinephrine Plasma Membrane Transport Proteins
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Serotonin Plasma Membrane Transport Proteins
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Tropanes
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Cocaine