Derivatives of 4-phenylpiperidine as substrates of rat brain monoamine oxidase

Ishkov A.G., Ermakov N.V., Mikerov S.V., Kliatskiĭ Yu.Yu., Miroshnichenko E.V.
PubMed Id: 1413624
Year: 1992  Volume: 38  Issue: 2  Pages: 25-28
A rate of utilization of 4-phenyl piperidine and its 12 derivatives by brain monoamine oxidase (MAO) was studied as compared with typical neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The enzyme was isolated from P2 synaptosomal fraction of brain corpus striatum of Sprague-Dawley rats. 10 drugs were oxidized in the MAO-catalyzed reaction with the rate close or similar to the MPTP oxidation while 6 of them exhibited the neurotoxic effect. Analysis of MAO inhibition, using 1 microM of chlorgyline and/or deprenyl, enabled to evaluate the contribution of MAO-A and MAO-B forms to utilization of 1 mM content of the substances studied. MAO-B was shown to oxidize preferably the drugs radicals of which were substituted at 3rd position of the piperidine ring, while MAO-A preferred the derivatives with radical substitution at 4th position. The rate of substrate oxidation was decreased distinctly after introduction of complete substituents into the 3rd and 4th positions of the nitrogenous heterocycle; at the same time, presence of cyclic fluorine-containing structures increased the rate of utilization, similar to that of MPTP oxidation. Derivatives of 4-phenyl piperidine, which contained in a number of drugs, were oxidized in the MAO-catalyzed reactions and might exhibit direct- or side-neurotoxic effects.
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Ishkov, A. G., Ermakov, N. V., Mikerov, S. V., Kliatskiĭ, Yu. Yu., Miroshnichenko, E. V. (1992). Derivatives of 4-phenylpiperidine as substrates of rat brain monoamine oxidase. Voprosy Meditsinskoi Khimii, 38(2), 25-28.
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