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Title

Impact of species-dependent differences on screening, design, and development of MAO B inhibitors

Authors
Novaroli, L.
Favre, Elisabeth
Carotti, Angelo
Leonetti, F.
Catto, M.
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Published in Journal of Medicinal Chemistry. 2006, vol. 49, no. 21, p. 6264-6272
Abstract The impact of species-dependent differences between human and rat MAO B on inhibitor screening was evidenced for two classes of compounds, coumarin and 5H-indeno[1,2-c]pyridazin-5-one derivatives. All examined compounds have shown a greater inhibitor potency toward human MAO B than toward rat MAO B. Moreover, no correlation was found between human and rat pIC(50) values. These divergences have important implications for the design and development of drugs involved in the MAO B metabolic pathway, suggesting that results obtained using rat enzyme cannot be extrapolated to human CNS, a priori. Indeed, the selection of a hit compound for lead generation could be different using human rather than rat enzyme. Moreover, the influence of substituents on the in vitro inhibition of human MAO B was markedly different between homogeneous series of coumarin and 5H-indeno[1,2-c]pyridazin-5-one derivatives, suggesting different binding modes, a hypothesis clearly supported by molecular docking simulations of inhibitors into the active site of human MAO B.
Keywords AnimalsBinding SitesCoumarins/*chemical synthesis/chemistry/pharmacologyDrug DesignHumansIndenes/*chemical synthesis/chemistry/pharmacologyLigandsMitochondrial Membranes/drug effects/enzymologyModels, MolecularMolecular StructureMonoamine Oxidase/*metabolismMonoamine Oxidase Inhibitors/*chemical synthesis/chemistry/pharmacologyProtein BindingPyridazines/*chemical synthesis/chemistry/pharmacologyRatsSpecies SpecificityStructure-Activity Relationship
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Other version: http://pubs.acs.org/doi/pdfplus/10.1021/jm060441e
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PMID: 17034132
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