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Synthesis and monoamine transporter binding properties of 2,3-cyclo analogues of 3beta-(4'-aminophenyl)-2beta-tropanemethanol.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2006 Jul 27; Vol. 49 (15), pp. 4589-94. - Publication Year :
- 2006
-
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.
- Subjects :
- Animals
Binding, Competitive
Cocaine chemical synthesis
Cocaine chemistry
Cocaine pharmacology
Crystallography, X-Ray
Hydrophobic and Hydrophilic Interactions
Models, Molecular
Molecular Structure
Radioligand Assay
Rats
Static Electricity
Structure-Activity Relationship
Tropanes chemistry
Tropanes pharmacology
Cocaine analogs & derivatives
Dopamine Plasma Membrane Transport Proteins metabolism
Norepinephrine Plasma Membrane Transport Proteins metabolism
Serotonin Plasma Membrane Transport Proteins metabolism
Tropanes chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 49
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 16854064
- Full Text :
- https://doi.org/10.1021/jm060287w