Novel 4-(aryloxy)tetrahydropyridine analogs of MPTP as monoamine oxidase A and B substrates.
The exceptionally good monoamine oxidase (MAO) substrate properties of several 4-(arylmethyl)-1-methyl-1,2,3,6-tetrahydropyridine derivatives related to the neurotoxin MPTP have prompted studies to evaluate the corresponding properties of tetrahydropyridine derivatives bearing heteroatom-linked groups at C-4. The expected dihydropyridinium metabolites generated from these MAO-A- and MAO-B-catalyzed oxidations of the 4-(aryloxy)tetrahydropyridine analogs were found to undergo rapid hydrolytic cleavage to yield the corresponding arenol and 1-methyl-2,3-dihydro-4-pyridone, a species that could be monitored spectrophotometrically. We have exploited this reaction sequence to probe the active sites of beef liver MAO-B and human placental MAO-A with a variety of 4-(aryloxy)-1-methyl-1,2,3,6-tetrahydropyridine derivatives. The results are discussed in relationship to recently published reports describing the MAO-A vs MAO-B selectivity of various 4-(arylmethyl)tetrahydropyridine derivatives.
Kalgutkar
A S
AS
Department of Chemistry, Virginia Polytechnic Institute and State University, Blacksburg 24061-0212.
Castagnoli
K
K
Hall
A
A
Castagnoli
N
N
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D002417:Cattle; D006801:Humans; D008099:Liver / Q000201:enzymology; D008995:Monoamine Oxidase / Q000378:metabolism*; D010920:Placenta / Q000201:enzymology; D011108:Polymers / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism*; D013379:Substrate Specificity
D011108:Polymers; D011725:Pyridines; C017027:arylox; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase