Novel N-substituted 3 alpha-[bis(4'-fluorophenyl)methoxy]tropane analogues: selective ligands for the dopamine transporter
| Autor: | Jae H. Wu, Jonathan L. Katz, Gregory E. Agoston, Clifford George, Sari Izenwasser, Richard H. Kline, Amy Hauck Newman |
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| Rok vydání: | 1998 |
| Předmět: |
Male
Models Molecular Stereochemistry Dopamine Nerve Tissue Proteins Motor Activity Crystallography X-Ray Ligands Chemical synthesis Binding Competitive Acylation chemistry.chemical_compound Mice Structure-Activity Relationship Cocaine Dopamine Uptake Inhibitors Drug Discovery medicine Animals Dopamine transporter Dopamine Plasma Membrane Transport Proteins Membrane Glycoproteins Bicyclic molecule biology Molecular Structure Brain Membrane Transport Proteins Tropane Receptors Muscarinic Benztropine Rats chemistry biology.protein Molecular Medicine Carrier Proteins medicine.drug Tropanes |
| Zdroj: | Journal of medicinal chemistry. 40(26) |
| ISSN: | 0022-2623 |
| Popis: | A series of N-substituted 3 alpha-[bis(4'-fluorophenyl)methoxy]tropane analogues has been prepared that function as dopamine uptake inhibitors. The N-methylated analogue of this series had a significantly higher affinity for the dopamine transporter than the parent compound, N-methyl-3 alpha- (diphenylmethoxy)tropane (benztropine, Cogentin). Yet like the parent compound, it retained high affinity for muscarinic receptors. A series of N-substituted compounds were prepared from nor-3 alpha-[bis(4'-fluorophenyl)methoxy]tropane via acylation followed by hydride reduction of the amide or by direct alkylation. All compounds containing a basic tropane nitrogen displaced [3H]WIN 35,428 at the dopamine transporter (Ki range = 8.5-634 nM) and blocked dopamine uptake (IC50 range = 10-371 nM) in rat caudate putamen, whereas ligands with a nonbasic nitrogen were virtually inactive. None of the compounds demonstrated high binding affinity at norepinephrine or serotonin transporters. Importantly, a separation of binding affinities for the dopamine transporter versus muscarinic m1 receptors was achieved by substitution of the N-methyl group with other N-alkyl or arylalkyl substituents (eg. n-butyl, allyl, benzyl, 3-phenylpropyl, etc.). Additionally, the most potent and selective analogue in this series at the dopamine transporter, N-(4"-phenyl-n-butyl)-3 alpha-[bis(4'-fluorophenyl)methoxy]tropane analogue failed to substitute for cocaine in rats trained to discriminate cocaine from saline. Potentially, new leads toward the development of a pharmacotherapeutic for cocaine abuse and other disorders affecting the dopamine transporter may be discovered. |
| Databáze: | OpenAIRE |
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