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dc.contributor.advisorBergh, J.J.
dc.contributor.advisorPetzer, J.P.
dc.contributor.advisorTerre'Blanche, G.
dc.contributor.authorPretorius, Anél
dc.date.accessioned2011-04-08T13:05:19Z
dc.date.available2011-04-08T13:05:19Z
dc.date.issued2008
dc.identifier.urihttp://hdl.handle.net/10394/4123
dc.descriptionThesis (Ph.D. (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2009.
dc.description.abstractThe parkinsonian inducing agent, 1-rnethyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), is a cyclic tertiary allylamine that is oxidized by monoamine oxidase B (MAO-B) at the ring a-carbon to yield the 1-rnethyl-4-phenyl-2,3-dihydropyridiniurn species (MPDP+). 1-Methyl-3-phenyl-3-pyrroline, another cyclic tertiary allylamine and 5-membered ring MPTP analogue, is also oxidized by MAO-B to yield the 2- electron oxidation product, 1-methyl-3-phenylpyrrole. By using the corresponding pyrroline-2,2,4,5,5-ds analogues as the deuterated substrates, the kinetic deuterium isotope effects on V max and V max/Km for the steady-state oxidation by baboon liver MAO-B was determined for l-methy1-3-phenyl-3-pyrroline and 1-methyl-3-(4- fluoropheny1)-3-pyrroline. The isotope effects for the two substrates were 4.29 and 3.98 on Vmax, and 5.71 and 3.37 on Vmax/Km, respectively. The values reported for the oxidation of MPTP by bovine liver MAO-B with MPTP-6,6-d2 as deuterated substrate are 3.55 for 0 (Vmax) and 8.01 for 0 (Vmax/Km). We conclude that the mechanism of the MAO-B-catalyzed oxidation of pyrrolinyl substrates is similar to that of the tetrahydropyridinyl substrates and that a carbon-hydrogen bond cleavage step is, at least partially, rate-determining. The saturated piperidinyl analogue of MPTP is not a MAO-B substrate; therefore it appears that the a-carbon 2-electron oxidation of cyclic tertiary aminyl substrates by MAO-B is dependent on the presence of the allylic 7t-bond. The 3,4-cyclopropyl analogue of MPTP, 3-methyl-6-phenyl-3-azabicyclo[4.1.0]heptane, is the only known saturated, cyclic tertiary amine substrate of MAO-B. As part of our ongoing investigation into the MAO-B substrate properties of 5-membered azacyclic systems, we have examined the interactions of the corresponding saturated pyrrolidinyl (1- methyl-3-phenylpyrrolidine) and 3,4-cyclopropyl (3-methyl-l-phenyl-3- azabicyclo[3.1.0]-hexane) analogues of 1-methyl-3-phenyl-3-pyrroline with MAO-B. We have also examined the possibility that these saturated substrates may act as neurotoxins in the C57BL/6 mouse. The results document that both the pyrrolidinyl [Km = 234 µM; Vmax = 8.37 nmol/(min-mg mitochondrial protein)] and the 3,4- cyclopropyl analogues [Km = 148 µM; VmBX = 16.9 nmol/(min-mg mitochondrial protein)] are efficiently oxidized by baboon liver MAO-B. Since striatal dopamine depletion was not observed while analogous treatment with MPTP resulted in 64-73% depletion, it can be concluded that, unlike MPTP, the cyclic tertiary amines examined here are not nigrostriatal toxins.
dc.publisherNorth-West University
dc.titleThe monoamine oxidase B substrate properties of selected pyrrolinyl analoguesen
dc.typeThesisen
dc.description.thesistypeDoctoral


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