title: The Synthesis and Evaluation of C7-Substituted α-Tetralone Derivatives as Inhibitors of Monoamine Oxidase.
abstract: Based on a previous report that α-tetralone (3,4-dihydro-2H-naphthalen-1-one) is a promising scaffold for the design of highly potent inhibitors of the enzyme, monoamine oxidase, the present study investigates the monoamine oxidase inhibitory properties of a synthetic series of fifteen C7-substituted α-tetralone derivatives. Arylalkyloxy substitution on C7 of the α-tetralone moiety yielded compounds with high inhibition potencies toward the human monoamine oxidase-B isoform with all compounds possessing IC50 values in the submicromolar range (0.00089-0.047 μm). The C7-substituted α-tetralones also were highly potent monoamine oxidase-A inhibitors with thirteen (of fifteen) compounds possessing IC50 values in the submicromolar range (0.010-0.741 μm). The α-tetralones were, however, in each instance selective for monoamine oxidase-B over the monoamine oxidase-A isoform. Dialyses of enzyme-inhibitor mixtures show that, while a representative inhibitor acts as a reversible monoamine oxidase-A inhibitor, inhibition of monoamine oxidase-B is not readily reversed by dialysis. Using a molecular modeling approach, possible binding orientations and interactions of selected α-tetralones with the active sites of the monoamine oxidases are also proposed. This study suggests that C7-substituted α-tetralones are promising monoamine oxidase inhibitors and may represent lead compounds for the development of therapies for Parkinson's disease and depression.
authors.affiliation: Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom, 2520, South Africa.
authors.forename: Lesetja J
authors.initials: LJ
authors.lastname: Legoabe
authors.affiliation: Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom, 2520, South Africa.
authors.forename: Anél
authors.initials: A
authors.lastname: Petzer
authors.affiliation: Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom, 2520, South Africa.|Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom, 2520, South Africa.
authors.forename: Jacobus P
authors.initials: JP
authors.lastname: Petzer
mesh_terms: D006801:Humans; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D044024:Tetralones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D008996:Monoamine Oxidase Inhibitors; D044024:Tetralones; D008995:Monoamine Oxidase
keywords: competitive; dialysis; inhibition; monoamine oxidase; reversible; α-tetralone