title: Vesicular monoamine transporter substrate/inhibitor activity of MPTP/MPP+ derivatives: a structure-activity study.
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.
authors.affiliation: Department of Chemistry, Wichita State University, Wichita, Kansas 67260-0051, USA.
authors.forename: D Shyamali
authors.initials: DS
authors.lastname: Wimalasena
authors.forename: Rohan P
authors.initials: RP
authors.lastname: Perera
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Heyen
authors.forename: Inoka S
authors.initials: IS
authors.lastname: Balasooriya
authors.forename: Kandatege
authors.initials: K
authors.lastname: Wimalasena
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D015655:1-Methyl-4-phenylpyridinium / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D002417:Cattle; D002837:Chromaffin Granules / Q000187:drug effects / Q000378:metabolism; D018360:Crystallography, X-Ray; D066298:In Vitro Techniques; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D050493:Vesicular Monoamine Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D050493:Vesicular Monoamine Transport Proteins; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015655:1-Methyl-4-phenylpyridinium