Mechanism-based inactivation of monoamine oxidases A and B by tetrahydropyridines and dihydropyridines.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its primary oxidation product, 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP+), are mechanism-based inhibitors of monoamine oxidases A and B. The pseudo-first-order rate constants for inactivation were determined for various analogues of MPTP and MPDP+ and the concentrations in all redox states were measured throughout the reaction. Disproportionation was observed for all the dihydropyridiniums, but non-enzymic oxidation was insignificant. The dihydropyridiniums were poor substrates for monoamine oxidase A and, consequently, inactivated the enzyme only slowly, despite partition coefficients lower than those for the tetrahydropyridines. For monoamine oxidase B, the dihydropyridiniums were more effective inactivators than the tetrahydropyridines. Substitutions in the aromatic ring had no major effect on the inactivation of monoamine oxidase B, but the 2'-ethyl- and 3'-chloro-substituted compounds were very poor mechanism-based inactivators of monoamine oxidase A. It is clear that both oxidation steps can generate the reactive species responsible for inactivation.
Krueger
M J
MJ
Department of Biochemistry and Biophysics, University of California, San Francisco 94143.
McKeown
K
K
Ramsay
R R
RR
Youngster
S K
SK
Singer
T P
TP
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D010084:Oxidation-Reduction; D011247:Pregnancy; D011726:Pyridinium Compounds / Q000378:metabolism / Q000494:pharmacology*; D013053:Spectrophotometry; D013379:Substrate Specificity
D008996:Monoamine Oxidase Inhibitors; D011726:Pyridinium Compounds; C044755:1-methyl-4-phenyl-2,3-dihydropyridinium; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase