A new class of powerful inhibitors of monamine oxidase A.
It is well established that 1-methyl-4-phenylpyridinium (MPP), the neurotoxic bioactivation product of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and most of its analogs are good competitive inhibitors of monoamine oxidase A, with Ki values in the micromolar range, but they inhibit monoamine oxidase B only at much higher concentrations. We report here the finding that alkyl derivatives of MPP+ substituted at the 4' position of the aromatic ring are considerably more effective reversible inhibitors of the A type enzyme, with Ki values in the nanomolar range (0.075-1.6 microM). They inhibit the B type enzyme only at 2 to 3 orders of magnitude higher concentrations (32-374 microM).
Jin
Y Z
YZ
Department of Biochemistry and Biophysics, University of California, San Francisco 94143.
Ramsay
R R
RR
Youngster
S K
SK
Singer
T P
TP
D015655:1-Methyl-4-phenylpyridinium / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D001667:Binding, Competitive; D004305:Dose-Response Relationship, Drug; D008928:Mitochondria / Q000187:drug effects*; D008996:Monoamine Oxidase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010920:Placenta / Q000187:drug effects*
D008996:Monoamine Oxidase Inhibitors; D015655:1-Methyl-4-phenylpyridinium