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.