title: 2-Arylthiomorpholine derivatives as potent and selective monoamine oxidase B inhibitors.
abstract: 2-Arylthiomorpholine and 2-arylthiomorpholin-5-one derivatives, designed as rigid and/or non-basic phenylethylamine analogues, were evaluated as rat and human monoamine oxidase inhibitors. Molecular docking provided insight into the binding mode of these inhibitors and rationalized their different potencies. Making the phenylethylamine scaffold rigid by fixing the amine chain in an extended six-membered ring conformation increased MAO-B (but not MAO-A) inhibitory activity relative to the more flexible alpha-methylated derivative. The presence of a basic nitrogen atom is not a prerequisite in either MAO-A or MAO-B. The best K(i) values were in the 10(-8)M range, with selectivities towards human MAO-B exceeding 2000-fold.
authors.affiliation: Department of Chemistry, Faculty of Sciences, University of Chile, Santiago, Chile. iturriag@uchile.cl
authors.forename: Susan
authors.initials: S
authors.lastname: Lühr
authors.forename: Marcelo
authors.initials: M
authors.lastname: Vilches-Herrera
authors.forename: Angélica
authors.initials: A
authors.lastname: Fierro
authors.forename: Rona R
authors.initials: RR
authors.lastname: Ramsay
authors.forename: Dale E
authors.initials: DE
authors.lastname: Edmondson
authors.forename: Miguel
authors.initials: M
authors.lastname: Reyes-Parada
authors.forename: Bruce K
authors.initials: BK
authors.lastname: Cassels
authors.forename: Patricio
authors.initials: P
authors.lastname: Iturriaga-Vásquez
mesh_terms: D000818:Animals; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000187:drug effects*; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats
chemical_list: D008996:Monoamine Oxidase Inhibitors; D009025:Morpholines; D008995:Monoamine Oxidase