Synthesis and Biological Evaluation of Tropane-like 1-{2-[Bis(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine (GBR 12909) Analogues
| Autor: | Ying Zhang, and Arthur E. Jacobson, Kenner C. Rice, David B. Joseph, Christina M. Dersch, Richard B. Rothman, J. L. Flippen-Anderson, Wayne D. Bowen |
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| Rok vydání: | 2001 |
| Předmět: |
Male
Serotonin Stereochemistry Dopamine Nerve Tissue Proteins In Vitro Techniques Crystallography X-Ray Piperazines Reuptake Rats Sprague-Dawley Structure-Activity Relationship chemistry.chemical_compound Dopamine Uptake Inhibitors Drug Discovery medicine Animals Moiety Dopamine transporter Serotonin Plasma Membrane Transport Proteins Dopamine Plasma Membrane Transport Proteins Membrane Glycoproteins biology Bicyclic molecule Receptor Muscarinic M1 Brain Membrane Transport Proteins Tropane Receptors Muscarinic Rats Piperazine chemistry biology.protein Molecular Medicine Carrier Proteins Reuptake inhibitor Tropanes medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 44:3937-3945 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | We have prepared azabicyclo[3.2.1] derivatives (C-3-substituted tropanes) that bind with high affinity to the dopamine transporter and inhibit dopamine reuptake. Within the series, 3-[2-[bis-(4-fluorophenyl)methoxy]ethylidene]-8-methyl-8-azabicyclo[3.2.1]octane (8) was found to have the highest affinity and selectivity for the dopamine transporter. These azabicyclo[3.2.1] (bridged piperidine) series of compounds differ from the well-known benztropines by a 2-carbon spacer between C-3 and a diarylmethoxy moiety. Interestingly, these new compounds demonstrated a much lower affinity for the muscarinic-1 site, at least a 100-fold decrease compared to benztropine. Replacing N-methyl with N-phenylpropyl in two of the compounds resulted in a 3-10-fold increase in binding affinity for the dopamine transporter. However, those compounds lost selectivity for the dopamine transporter over the serotonin transporter. Replacement of the ether oxygen in the diarylmethoxy moiety with a nitrogen atom gave relatively inactive amines, indicating the important role which is played by the ether oxygen in transporter binding. Reduction of the C-3 double bond in 8 gave 3 alpha-substituted tropanes, as shown by X-ray crystallographic analyses of 11, 12, and 19. The 3 alpha-substituted tropanes had lower affinity and less selectivity than the comparable unsaturated ligands. |
| Databáze: | OpenAIRE |
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