Inhibition of types A and B monoamine oxidase by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was studied as an inhibitor of type A monoamine oxidase (MAO) acting on [14C]serotonin as substrate and of type B MAO acting on [14C]phenylethylamine as substrate. MPTP was a reasonably potent (Ki = 9 microM), competitive, reversible inhibitor of M...
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Published in | The Journal of pharmacology and experimental therapeutics Vol. 232; no. 3; p. 696 |
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Main Authors | , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Pharmacology and Experimental Therapeutics
01.03.1985
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Subjects | |
Online Access | Get full text |
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Summary: | 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was studied as an inhibitor of type A monoamine oxidase (MAO) acting on
[14C]serotonin as substrate and of type B MAO acting on [14C]phenylethylamine as substrate. MPTP was a reasonably potent (Ki
= 9 microM), competitive, reversible inhibitor of MAO-A from rat brain in vitro. MPTP given at a 30-mg/kg i.p. dose antagonized
the irreversible inactivation of MAO-A in rat brain by pargyline, indicating that it inhibited MAO-A in vivo. At that same
dose, MPTP prevented the conversion of dopamine released by Ro 4-1284 to 3,4-dihydroxyphenylacetic acid and attenuated its
conversion to homovanillic acid. Because dopamine is mainly deaminated by MAO-A, at least in rodent brain, inhibition of MAO-A
by MPTP might play some part in its production of persistent effects on striatal dopamine neurons such as protection of intraneuronal,
extragranular dopamine from deamination. MPTP was less potent as an inhibitor of MAO-B from rat brain in vitro (Ki = 106 microM).
In contrast to the inhibition of MAO-A, the inhibition of MAO-B by MPTP showed noncompetitive kinetics, was not fully reversible
by dialysis and was time dependent. The characteristics of MAO-B inhibition are like those of a kcat inhibitor, which is acted
upon by an enzyme to produce a reactive product that can covalently attach to the enzyme or other macromolecules. |
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ISSN: | 0022-3565 1521-0103 |