1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a powerful neurotoxin which induces symptoms of Parkinson's disease in humans and other primates. Presently, details of the fundamental molecular mechanism of the monoamine oxidase B-mediated metabolism of MPTP (a tertiary amine) are not completely understood. Preliminary data suggest the intermediacy of a free radical pathway for the process. The research described herein is part of a continuing effort that seeks to elucidate the energetics and molecular dynamics of the reaction between a broad range of structurally diverse tertiary amines and reactive heteroatom based free radicals. Detailed characterization of the aforementioned general reaction will yield specific information relevant to the fundamental molecular mechanism of the enzymatic oxidation of (MPTP) and its analogs. The free radical tert-butoxyl has been widely used as a model of reactive oxygen based radical in biological systems.. In recent studies, this free radical has been demonstrated to exhibit very low selectivity in hydrogen atom abstraction reactions with tertiary amines, and its utility as a model abstracting species has been called into question. This research will therefore investigate the utility of other heteroatom (specifically nitrogen and sulfur) based free radicals as potential models for abstracting species in biological systems. The absolute rate constants and selectivity for the abstraction of hydrogen atom from the amines by nitrogen and sulfur based radicals will be determined by kinetic laser flash spectroscopy. The reaction dynamics will be characterized by obtaining Arrhenius parameters(activation energies [Ea] and A factors) for each amine by studying the variation in reaction rates between 10 degrees Centigrade and 70 degrees Centigrade. The kinetic deuterium isotope effect for all the abstraction reactions will be evaluated using deuterated amines. These data will significantly improve our understanding of the use of appropriate radical species as models for enzymatic radical oxidations of amines.
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