Document Detail

Synthesis and monoamine transporter binding properties of 2,3-cyclo analogues of 3beta-(4'-aminophenyl)-2beta-tropanemethanol.
MedLine Citation:
PMID:  16854064     Owner:  NLM     Status:  MEDLINE    
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.
F Ivy Carroll; Bruce E Blough; Xiaodong Huang; Zhe Nie; S Wayne Mascarella; Jeffrey Deschamps; Hernán A Navarro
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  49     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2006 Jul 
Date Detail:
Created Date:  2006-07-20     Completed Date:  2006-08-31     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4589-94     Citation Subset:  IM    
Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, North Carolina 27709-2194, USA.
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MeSH Terms
Binding, Competitive
Cocaine / analogs & derivatives*,  chemical synthesis,  chemistry,  pharmacology
Crystallography, X-Ray
Dopamine Plasma Membrane Transport Proteins / metabolism*
Models, Molecular
Molecular Structure
Norepinephrine Plasma Membrane Transport Proteins / metabolism*
Radioligand Assay
Serotonin Plasma Membrane Transport Proteins / metabolism*
Static Electricity
Structure-Activity Relationship
Tropanes / chemical synthesis*,  chemistry,  pharmacology
Grant Support
Reg. No./Substance:
0/4,5,6,7,8,9,10,11,13,17a,18,19,20,21,22,22a-hexadecahydro-23-methyl-14,17-etheno-19,22-imino-1H-cyclohept(c)(1,9)oxaazacyclononadecine-3,12-dione; 0/5,6,7,8,10,14a,15,16,17,18,19,19a-dodecahydro-20-methyl-11,14-etheno-16,19-iminocyclohept(c)(1,9)oxaazacyclohexadecine-3,9(1H,4H)-dione; 0/Dopamine Plasma Membrane Transport Proteins; 0/Norepinephrine Plasma Membrane Transport Proteins; 0/Serotonin Plasma Membrane Transport Proteins; 0/Tropanes; 50-36-2/Cocaine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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