Synthesis and biological evaluation of MAO-A selective 1,4-disubstituted-1,2,3,6-tetrahydropyridinyl substrates.
Many mammalian tissues express both the A and B forms of monoamine oxidase (MAO), flavoenzymes that catalyze the oxidative deamination of a variety of endogenous and exogenous amines and the ring alpha-carbon oxidative bioactivation of neurotoxic 1,4-disubstituted-1,2,3,6-tetrahydropyridinyl derivatives. Substrates selective for MAO-A that display good kinetic and spectroscopic properties would be of value for developing quantitative assays for MAO-A in tissues that express both the A and B forms of the enzyme. This paper describes the synthesis of several 1-substituted-4-(1-methylpyrrol-2-yl)-1,2,3,6-tetrahydropyridinyl derivatives. Kinetic parameters and MAO-A selectivity indicate that 1-allyl- and 1-propyl-4-(1-methylpyrrol-2-yl)-1,2,3,6-tetrahydropyridine should be good candidates to develop a robust spectrophotometric-based assay that is selective for MAO-A.
Department of Chemistry, Virginia Polytechnic Institute and State University, 107 Davidson Hall, Blacksburg, VA 24061-0212, USA.
Philippe
P
Bissel
Mark C
MC
Bigley
Kay
K
Castagnoli
Neal
N
Castagnoli
D006801:Humans; D007700:Kinetics; D008928:Mitochondria / Q000201:enzymology; D008930:Mitochondria, Liver / Q000201:enzymology; D008995:Monoamine Oxidase / Q000032:analysis / Q000378:metabolism*; D010920:Placenta / Q000201:enzymology / Q000648:ultrastructure; D011725:Pyridines / Q000378:metabolism*; D013057:Spectrum Analysis; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D011725:Pyridines; D008995:Monoamine Oxidase