Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS023066-03
Application #
3406111
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1986-02-01
Project End
1988-09-30
Budget Start
1988-02-01
Budget End
1988-09-30
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost

  Institution

Name
University of California San Francisco
Department
Type
Schools of Pharmacy
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143

  Publications

Rollema, H; Skolnik, M; D'Engelbronner, J et al. (1994) MPP(+)-like neurotoxicity of a pyridinium metabolite derived from haloperidol: in vivo microdialysis and in vitro mitochondrial studies. J Pharmacol Exp Ther 268:380-7
Subramanyam, B; Rollema, H; Woolf, T et al. (1990) Identification of a potentially neurotoxic pyridinium metabolite of haloperidol in rats. Biochem Biophys Res Commun 166:238-44
Ottoboni, S; Carlson, T J; Trager, W F et al. (1990) Studies on the cytochrome P-450 catalyzed ring alpha-carbon oxidation of the nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Chem Res Toxicol 3:423-7
Rollema, H; Johnson, E A; Booth, R G et al. (1990) In vivo intracerebral microdialysis studies in rats of MPP+ analogues and related charged species. J Med Chem 33:2221-30
Naiman, N; Rollema, H; Johnson, E et al. (1990) Studies on 4-benzyl-1-methyl-1,2,3,6-tetrahydropyridine, a nonneurotoxic analogue of the parkinsonian inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Chem Res Toxicol 3:133-8
Booth, R G; Castagnoli Jr, N; Rollema, H (1989) Intracerebral microdialysis neurotoxicity studies of quinoline and isoquinoline derivatives related to MPTP/MPP+. Neurosci Lett 100:306-12
Rollema, H; Alexander, G M; Grothusen, J R et al. (1989) Comparison of the effects of intracerebrally administered MPP+ (1-methyl-4-phenylpyridinium) in three species: microdialysis of dopamine and metabolites in mouse, rat and monkey striatum. Neurosci Lett 106:275-81
Ottoboni, S; Caldera, P; Trevor, A et al. (1989) Deuterium isotope effect measurements on the interactions of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine with monoamine oxidase B. J Biol Chem 264:13684-8
Johnson, E A; Wu, E Y; Rollema, H et al. (1989) 1-methyl-4-phenylpyridinium (MPP+) analogs: in vivo neurotoxicity and inhibition of striatal synaptosomal dopamine uptake. Eur J Pharmacol 166:65-74
Youngster, S K; McKeown, K A; Jin, Y Z et al. (1989) Oxidation of analogs of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by monoamine oxidases A and B and the inhibition of monoamine oxidases by the oxidation products. J Neurochem 53:1837-42

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