Vesicular Monoamine Transporter Substrate/Inhibitor Activity of MPTP/MPP+ Derivatives: A Structure–Activity Study
| Autor: | D. Shyamali Wimalasena, Bruce J. Heyen, Inoka S. Balasooriya, Kandatege Wimalasena, Rohan P. Perera |
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| Rok vydání: | 2008 |
| Předmět: |
Models
Molecular 1-Methyl-4-phenylpyridinium In Vitro Techniques Pharmacology Crystallography X-Ray Structure-Activity Relationship chemistry.chemical_compound Dopamine Drug Discovery medicine Animals Chromaffin Granules Active metabolite Chemistry MPTP Dopaminergic Substrate (chemistry) In vitro nervous system diseases Vesicular monoamine transporter nervous system Biochemistry 1-Methyl-4-phenyl-1 2 3 6-tetrahydropyridine Vesicular Monoamine Transport Proteins Catecholamine Molecular Medicine Cattle medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 51:760-768 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm070875p |
| Popis: | The active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), N-methyl-4-phenylpyridinium (MPP(+)), selectively destroys the dopaminergic neurons and induces the symptoms of Parkinson's disease. Inhibition of mitochondrial complex I and/or the perturbation of dopamine metabolism through cellular and granular accumulation have been proposed as some of the major causes of neurotoxicity. In the present study we have synthesized and characterized a number of MPTP and MPP(+) derivatives that are suitable for the comparative neurotoxicity and complex I inhibition versus dopamine metabolism perturbation studies. Structure-activity studies with bovine chromaffin granule ghosts show that 3'-hydroxy-MPP(+) is one of the best known substrates for the vesicular monoamine transporter (VMAT). A series of compounds that combine the structural features of MPP(+) and a previously characterized VMAT inhibitor, 3-amino-2-phenyl-propene, have been identified as the most effective VMAT inhibitors. These derivatives have been used to define the structural requirements of the VMAT substrate and inhibitor activities. |
| Databáze: | OpenAIRE |
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