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Model studies on mechanisms of selected chemically-induced neurological disorders

Singh, Malvinder Pal
http://rave.ohiolink.edu/etdc/view?acc_num=case1059056627

Abstract Details

1990, Doctor of Philosophy, Case Western Reserve University, Chemistry.
1. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced Parkinsonism. The dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) arises from its monoamine oxidase (MAO)-mediated metabolite, 1-methyl-4-phenylpyridinium cation (MPP+), which kills cells by virtue of a persistent inhibition of mitochondrial respiration. Despite it being a rather weak inhibitor of electron transport, MPP+ is an effective inhibitor on intact mitochondria because it undergoes energy-dependent accumulation inside the matrix. Replacement of the 4-phenyl ring of MPP+ by a variety of lipophilic substituents preserves the inhibition patterns of MPP+, supportive of a Nernstian passive diffusion of the pyridinium cations across the mitochondrial inner membrane in response to the transmembrane potential (Δψ). Various bis-pyridine analogs of MPP+ in neutral, monocationic, and dicationic forms were synthesized, and a greater accumulation-dependent enhancement of inhibition was observed for the more lipophilic dictations than for the corresponding monocations, consistent with the Nernstian prediction. Seven MPTP analogs were synthesized to probe additional structural r equirements for MAO oxidation. Oxidation of 1-methyl-4-benzyl-1,2,3,6-tetrahydropyridine does not lead to the corresponding 1-methyl-4-benzylpyridinium, because deprotonation of the initially generated intermediate 1-methyl-4-benzyl-2,3-dihydropyridinium gives an exocyclic dienamine, rather than the endocyclic dienamine required for oxidation to the pyridinium stage. 2. γ-Diketone-induced peripheral axonopathies. The current study attempted to achieve a mechanistic distinction between the two theories for γ-diketone neurotoxicity, namely pyrrolation of neurofilaments (NF) or pyrrole-autoxidation-induced cross-linking of NF, through the use of two fluorinated hexanediones, 1,1,1-trifluoro-2,5-hexanedione and 3-(trifluoromethyl)-2,5-hexanedione. The latter was found to form pyrroles more rapidly than 2,5-hexanedione with model primary amines, but the resulting pyrroles were found to be resistant toward oxidation 3. Mechanism-based inhibition of copper amine oxidases by β-aminopropionitrile (BAPN) and cyclopropylamines. 3,5-Di-t-butyl-1,2-benzoquinone and 4,7-phenanthroline-5,6-dione were used as models for pyrroloquinoline quinone (PQQ)-mediated conversion of primary amines to aldehydes, catalyzed by copper amine oxidases. We showed that the above amine inactivators, and other related amines (e.g., 1-phenylcyclopropylamine), result in a rechanneling of the normal PQQ-mediated transamination mechanism. BAPN results in a hydrolytically-metastable β-cyanoenamine, and cyclopropylamines lead to ring-opened adducts via non-homolytic processes
Lawrence Sayre (Advisor)
232 p.
Chemistry, Organic
Neurological disorders; chemically-induced mechanisms

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Citations

  • Singh, M. P. (1990). Model studies on mechanisms of selected chemically-induced neurological disorders [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1059056627

    APA Style (7th edition)

  • Singh, Malvinder. Model studies on mechanisms of selected chemically-induced neurological disorders. 1990. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1059056627.

    MLA Style (8th edition)

  • Singh, Malvinder. "Model studies on mechanisms of selected chemically-induced neurological disorders." Doctoral dissertation, Case Western Reserve University, 1990. http://rave.ohiolink.edu/etdc/view?acc_num=case1059056627

    Chicago Manual of Style (17th edition)

case1059056627
439
© 1990, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.