Monoamine oxidase A and B substrates: Probing the pathway for drug development

摘要

Drug-discovery and-development efforts focused on the MAOs have increased at an accelerated rate over the past decade. Since the first crystal structure of human MAO-B was solved in 2002, over 40 additional structures have been reported and have helped define new, or confirm speculative, binding modes of inhibitors. The detailed mechanism of the MAO-catalyzed oxidation of amine substrates has not been fully elucidated, but its significance is central in the development of new mechanism-based inactivators. Novel fungal MAO-N variants derived from directed evolution strategies are enabling the production of new chiral amine products. Robust assays have been established for measuring MAO status in tissue and cells, while improved MAO radioligands are being deployed for PET imaging studies. This review will attempt to highlight the more recent and salient aspects of MAO research in drug discovery and development, with emphasis on substrates 'probing the pathway'.