Potent in vivo but not in vitro inhibition of monoamine oxidase by 3-chloro-alpha-phenylpyrazinemethanol.
3-Chloro-alpha-phenylpyrazinemethanol (3-CPM) inhibited monoamine oxidase (MAO) types A and B in vivo in mouse brain, heart and liver. The inhibition was dose-dependent at doses of 0.3-32 mg/kg i.p. and occurred within 1 h after the compound was injected. 3-CPM was a very weak inhibitor of mouse brain mitochondrial MAO activity in vitro, even when preincubated with the enzyme; MAO-A was inhibited only about 50% at a high concentration of 3-CPM (1 mM), and MAO-B was inhibited even less. After a 10 mg/kg i.p. dose of 3-CPM in mice, both MAO-A and MAO-B were inhibited at day 1, but activity had largely recovered within a few days in brain, liver and heart. 3-CPM at doses of 1, 3, 10 and 32 mg/kg i.p. caused dose-dependent antagonism of the depletion of striatal dopamine and of cortical norepinephrine by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. 3-CPM is therefore a potent inhibitor of MAO-A and of MAO-B in mice in vivo despite its weak effect on the enzyme in vitro. A metabolite of the drug may be involved in the in vivo effects.
Fuller
R W
RW
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285.
Hemrick-Luecke
S K
SK
Ward
J S
JS
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D001592:Benzyl Alcohols / Q000494:pharmacology*; D001921:Brain / Q000201:enzymology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009206:Myocardium / Q000201:enzymology; D009638:Norepinephrine / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*
D001592:Benzyl Alcohols; D007527:Isoenzymes; D008996:Monoamine Oxidase Inhibitors; D011719:Pyrazines; C081541:3-chloro-alpha-phenylpyrazinemethanol; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase; D004298:Dopamine; D009638:Norepinephrine