BIOACTIVATION OF TERT-ALLYLAMINES MPTP TO NEUROTOXINS

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The tertiary allylamine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) selectively destroys the dopamine containing neurons of the nigrostriatal system in humans and a variety of experimental animals. The mechanism by which MPTP expresses its neurotoxicity has been shown to involve brain monoamine oxidase which catalyzes the oxidation of this compound to the corresponding 2,3-dihydropyridinium species. In order to document more fully the molecular events responsible for MPTP's toxicity, we propose to undertake the chemical and biochemical characterization of the monoamine oxidase catalyzed oxidation of MPTP and selected structurally related tertiary allylamines. Specifically we propose to study (1) the bioorganic mechanism of this reaction, (2) the in vitro metabolic profiles and kinetic parameters of the MAO catalyzed biotransformation of the proposed MPTP analogs and (3) the neurotoxic potential of these analogs in the mouse model. The results of these studies should help to identify those structural parameters which are required for this type of MAO substrate and to characterize the contribution which the MAO catalyzed oxidation of MPTP makes to the complex of biological events responsible for the MPTP induced destruction of nigrostriatal cells.