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- Title
The Synthesis and Evaluation of C7-Substituted α-Tetralone Derivatives as Inhibitors of Monoamine Oxidase.
- Authors
Legoabe, Lesetja J.; Petzer, Anél; Petzer, Jacobus P.
- Abstract
Based on a previous report that α-tetralone (3,4-dihydro-2 H-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 μ m). 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 μ m). 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.
- Subjects
TETRALONES; CHEMICAL derivatives; MONOAMINE oxidase; MOLECULAR models; PARKINSON'S disease treatment; MENTAL depression; THERAPEUTICS
- Publication
Chemical Biology & Drug Design, 2015, Vol 86, Issue 4, p895
- ISSN
1747-0277
- Publication type
Article
- DOI
10.1111/cbdd.12508