Vesicular Monoamine Transporter Substrate/Inhibitor Activity of MPTP/MPP+ Derivatives: A Structure–Activity Study

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• 作者：D. Shyamali Wimalasena ; Rohan P. Perera ; Bruce J. Heyen ; Inoka S. Balasooriya ; Kandatege Wimalasena
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：February 28, 2008
• 年：2008
• 卷：51
• 期：4
• 页码：760 - 768
• 全文大小：308K
• 年卷期：v.51,no.4(February 28, 2008)
• ISSN：1520-4804

文摘

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.