Catalysis & inhibition issues associated with Monoamine Oxidase (MAO). How unusually low α-C-H bond dissociation energies may open the door to single electron transfer

Abstract

CH Bond dissociation energies for a unique selection of tertiary amines that are known substrates or inhibitors of monoamine oxidase have been calculated using density functional theory. These amines are unusual because they are the only tertiary amines that exhibit MAO substrate or inhibitor behavior. The unique structural feature common to these specific compounds is an sp3-hybridized CH2 moiety, which is α-both to nitrogen and an C=C or CC. The stabilization afforded the resulting radicals by extended delocalization dramatically lowers both the CH bond strength of the substrate (R-H → R· + H·) and pKa of the corresponding radical cation (RH·+ → R· + H+). This interplay of structure and thermodynamics may provide the driving force for an electron transfer mechanism for MAO catalysis and inhibition.