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.
Twenty analogs of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were tested for their capacity to be oxidized by pure monoamine oxidase-A (MAO-A) prepared from human placenta and pure monoamine oxidase-B (MAO-B) prepared from beef liver. Several of the MPTP analogs were very good substrates for MAO-A, for MAO-B, or for both and had low Km values and high turnover numbers. These values were similar to or even better than those of kynuramine and benzylamine, good substrates for MAO-A and MAO-B, respectively. MPTP had relatively low Km values for oxidation by both MAO-A and MAO-B. In contrast, the turnover number for MPTP oxidation by MAO-B was considerably higher than the value for MAO-A. The corresponding pyridinium species of MPTP and several of the MPTP analogs inhibited MAO-A competitively with Ki values at micromolar concentrations; in contrast the pyridinium species inhibited MAO-B competitively at considerably higher concentrations (i.e., 100 microM or greater Ki values). The data provide information concerning the structural requirements for the oxidation of tetrahydropyridines by MAO-A and MAO-B and the inhibition of these enzymes by pyridiniums.
Youngster
S K
SK
Department of Neurology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway 08854.
McKeown
K A
KA
Jin
Y Z
YZ
Ramsay
R R
RR
Heikkila
R E
RE
Singer
T P
TP
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives* / Q000378:metabolism*; D000818:Animals; D007527:Isoenzymes / Q000378:metabolism*; D007700:Kinetics; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*; D010084:Oxidation-Reduction; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D007527:Isoenzymes; D008996:Monoamine Oxidase Inhibitors; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase