Studies of the in vitro oxidation of 1-methyl-4-(1-methylpyrrol-2-yl)-4-piperidinol and its dehydration product 1,2,3,6-tetrahydro-1-methyl-4-(methylpyrrol-2-yl) pyridine by human monoamine oxidases A and B.
The ability of highly purified preparations of human monoamine oxidase A and B (MAO A and B) to utilize 1-methyl-4-(1-methylpyrrol-2-yl)-4-piperidinol (MMPP) and its dehydration product 1,2,3,6-tetrahydro-1-methyl-4-(methylpyrrol-2-yl) pyridine (TMMP) as substrates was investigated. The results showed that TMMP was a substrate for both forms of MAO with Km,app values of approximately 60 microM. However, MAO B had a Vmax,app for TMMP about 30-fold greater than MAO A. Additional studies revealed that MMPP was a poor substrate of only MAO B (Km,app = 9.5 mM) and that acid treatment of MMPP led to the formation of a product that could be readily oxidized by both MAO A and B. Similar acid pretreatment of TMMP yielded a product that was a much poorer substrate for MAO B than the parent compound. These results may partially explain why orally administered MMPP produces neurotoxicity in monkeys and TMMP fails to induce chemical parkinsonism.
Bembenek
M E
ME
Division of Medicinal Chemistry, College of Pharmacy, University of Texas, Austin 78712.
D005260:Female; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism*; D010084:Oxidation-Reduction; D010880:Piperidines / Q000378:metabolism*; D010920:Placenta / Q000201:enzymology; D011247:Pregnancy; D011725:Pyridines / Q000378:metabolism*; D013056:Spectrophotometry, Ultraviolet; D013379:Substrate Specificity
D010880:Piperidines; D011725:Pyridines; C053572:1-methyl-4-(methylpyrrol-2-yl)-1,2,3,6-tetrahydropyridine; C053710:1-methyl-4-(1-methylpyrrol-2-yl)-4-piperidinol; D008995:Monoamine Oxidase