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The Synthesis and Evaluation of C7‐Substituted α ‐Tetralone Derivatives as Inhibitors of Monoamine Oxidase
Author(s) -
Legoabe Lesetja J.,
Petzer Anél,
Petzer Jacobus P.
Publication year - 2015
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12508
Subject(s) - monoamine oxidase , chemistry , tetralone , monoamine neurotransmitter , monoamine oxidase a , tetralones , ic50 , biochemistry , stereochemistry , enzyme , in vitro , serotonin , receptor
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 IC 50 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 IC 50 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.