Synthesis and Monoamine Transporter Binding Properties of 2,3-Cyclo Analogues of 3β-(4‘-Aminophenyl)-2β-tropanemethanol
| Autor: | Carroll Fi, Jeffrey R. Deschamps, S. W. Mascarella, Bruce E. Blough, Zhe Nie, Xiaodong Huang, Hernán A. Navarro |
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| Rok vydání: | 2006 |
| Předmět: |
Models
Molecular Sebacic acid Stereochemistry Static Electricity Crystallography X-Ray Binding Competitive Chemical synthesis Radioligand Assay Structure-Activity Relationship chemistry.chemical_compound Cocaine Amide Drug Discovery Animals Serotonin Plasma Membrane Transport Proteins Dopamine Plasma Membrane Transport Proteins Norepinephrine Plasma Membrane Transport Proteins Molecular Structure Monoamine transporter biology Tropane Rats Pimelic acid chemistry biology.protein Lactam Molecular Medicine Hydrophobic and Hydrophilic Interactions Linker Tropanes |
| Zdroj: | Journal of Medicinal Chemistry. 49:4589-4594 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm060287w |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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