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    Vesicular monoamine transporter substrate/inhibitor activity of MPTP/MPP+ derivatives: a structure-activity study

    Date
    2008-02-28
    Author
    Wimalasena, D. Shyamali
    Perera, Rohan P.
    Heyen, Bruce J.
    Balasooriya, Inoka S.
    Wimalasena, Kandatege
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    Citation
    Journal of medicinal chemistry. 2008 Feb 28; 51(4): 760-8.
    Abstract
    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.
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    Click on the DOI link below to access the article (may not be free).
    URI
    http://dx.doi.org/10.1021/jm070875p
    http://hdl.handle.net/10057/4434
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