Indanones As High‐Potency Reversible Inhibitors of Monoamine Oxidase

Abstract

Recent reports document that α-tetralone (3,4-dihydro-2H-naphthalen-1-one) is an appropriate scaffold for the design of high-potency monoamine oxidase (MAO) inhibitors. Based on the structural similarity between α-tetralone and 1-indanone, the present study involved synthesis of 34 1-indanone and related indane derivatives as potential inhibitors of recombinant human MAO-A and MAO-B. The results show that C6-substituted indanones are particularly potent and selective MAO-B inhibitors, with IC50 values ranging from 0.001 to 0.030 μM. C5-Substituted indanone and indane derivatives are comparatively weaker MAO-B inhibitors. Although the 1-indanone and indane derivatives are selective inhibitors of the MAO-B isoform, a number of homologues are also potent MAO-A inhibitors, with three homologues possessing IC50 values <0.1 μM. Dialysis of enzyme-inhibitor mixtures further established a selected 1-indanone as a reversible MAO inhibitor with a competitive mode of inhibition. It may be concluded that 1-indanones are promising leads for the design of therapies for neurodegenerative and neuropsychiatric disorders such as Parkinson's disease and depression.

The evaluation of 1,4-benzoquinones as inhibitors of human monoamine oxidase

“…The reversibility of MAO inhibition by selected 1,4-benzoquinones (4, 5a, 5b, and 5d) were examined by dialysis according to the literature protocol [39]. Slide-A-Lyzer® dialysis cassettes (Thermo Scientific) with a molecular weight cut-off of 10 000 and a sample volume capacity of 0.5-3 mL were used for these studies.…”

“…Both reversible and irreversible inhibitors of MAO-B, on the other hand, do not cause tyramine-induced changes in blood pressure and these agents have good safety profiles[16]. To investigate the reversibility of MAO inhibition by the 1,4-benzoquinones, mixtures containing the MAO enzymes and test inhibitors were incubated for 15 min and subsequently dialysed for 24 h[39]. The concentrations of the test inhibitor in these mixtures were equal to 4 × IC50 for the inhibition of a particular MAO isoform.…”

Monoamine oxidase inhibitory activities of heterocyclic chalcones

“…41,42 For both MAO isoforms, kynuramine served as enzyme substrate. Kynuramine is metabolised by the MAOs to yield 4-hydroxyquinoline, a metabolite which fluoresces in alkaline media.…”

Synthesis of 1-indanones with a broad range of biological activity

“…In this way, scientists have synthesized C5- and C6-alkoxy and benzyloxy-substituted 1-indanones by the alkylation reaction of 5-hydroxy-1-indanone or 6-hydroxy-1-indanone with various alkyl or benzyl bromides. These 1-indanone derivatives are potential inhibitors of two separate isoforms of monoamine oxidases: MAO-A and MAO-B [124]. Monoamine oxidases (MAO) are mitochondrial enzymes that catalyze two-electron oxidation of amine substrates.…”