title: Impact of species-dependent differences on screening, design, and development of MAO B inhibitors.
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.
authors.affiliation: LCT--Pharmacochemistry, School of pharmaceutical sciences, University of Geneva, University of Lausanne, Suisse.
authors.forename: Laura
authors.initials: L
authors.lastname: Novaroli
authors.forename: Antoine
authors.initials: A
authors.lastname: Daina
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Favre
authors.forename: Juan
authors.initials: J
authors.lastname: Bravo
authors.forename: Angelo
authors.initials: A
authors.lastname: Carotti
authors.forename: Francesco
authors.initials: F
authors.lastname: Leonetti
authors.forename: Marco
authors.initials: M
authors.lastname: Catto
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Carrupt
authors.forename: Marianne
authors.initials: M
authors.lastname: Reist
mesh_terms: D000818:Animals; D001665:Binding Sites; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D066298:In Vitro Techniques; D007192:Indenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013045:Species Specificity; D013329:Structure-Activity Relationship
chemical_list: D003374:Coumarins; D007192:Indenes; D008024:Ligands; D008996:Monoamine Oxidase Inhibitors; D011724:Pyridazines; D008995:Monoamine Oxidase