Synthesis and MAO-B substrate properties of 1-methyl-4-heteroaryl-1,2,3,6-tetrahydropyridines.
The parkinsonian inducing drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is bioactivated in a reaction catalyzed by the flavoenzyme monoamine oxidase B (MAO-B) to form the corresponding dihydropyridinium and subsequently pyridinium metabolites. As part of our ongoing studies to characterize the structural features responsible for this unexpected biotransformation, we have examined the MAO-B substrate properties of a variety of MPTP analogues bearing various heteroaryl groups at the 4-position of the tetrahydropyridinyl ring. The newly synthesized analogues are 4-(1-methylimidazol-2-yl)-, 4-(3-methylfuran-2-yl)-, 4-(3-methylthien-2-yl)-, 4-(3,4-dimethylpyrrol-1-yl)-, 4-(3-methylpyrrol-2-yl)-, and 4-(1,3-dimethylpyrrol-2-yl)-1-methyl-1,2,3,6-tetrahydropyridine. Except for the 4-(1-methylimidazol-2-yl) analogue, all compounds displayed good to excellent substrate properties. The 1-methyl-4-(3-methylfuran-2-yl) analogue is the most active member of this series with a kcat/Km value greater than 8,500 min(-1)mM(-1). The results of these studies are discussed in terms of catalytic pathways proposed for MAO-B.
Yu
J
J
Department of Chemistry, Virginia Polytechnic Institute and State University, Blacksburg 24061-0212, USA.
Castagnoli
N
N
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis*; D007700:Kinetics; D008956:Models, Chemical; D008995:Monoamine Oxidase / Q000378:metabolism*; D013053:Spectrophotometry
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase