An investigation of indanone derivatives as inhibitors of monoamine oxidase
Abstract
MAO-A and MAO-B are two isoforms of mitochondrial monoamine oxidase (MAO) that are responsible for the deamination of various monoamine substrates. For example tyramine and dopamine are metabolised by both MAO isoforms. MAO-A specifically metabolises noradrenaline and serotonin, while MAO-B metabolises exogenous amines such as benzylamine and 2-phenylethylamine. MAO-B is the dominant isoform in the striatum and hypothalamus of the human brain and inhibitors of this isoform are mainly indicated in Parkinson’s disease, while MAO-A dominates the periphery with depression as the main indication for MAO-A inhibitors. Irreversible inhibition of MAO-A may lead to the “cheese reaction” (when taken with tyramine rich foods) or serotonin syndrome (when administered with serotonin-elevating drugs). It is therefore essential to develop highly selective MAO-B inhibitors to eliminate these potentially fatal side effects of irreversible MAO-A inhibition.
Investigation of 1-indanone derivatives is suggested for this purpose as it is structurally similar to previously tested α-tetralones and 1-indanones that exhibited potent and selective MAO-B inhibition. Potent MAO-B inhibition was particularly displayed by α-tetralone inhibitors that were substituted on C6 and C7. In this study 1-indanone was substituted on C5 and C6 (the analogous positions to C6 and C7 of α-tetralone) with the anticipation that this will yield highly potent and specific inhibitors of MAO-B. The structure of 1-indanone is also similar to that of rasagiline, a highly potent MAO-B inhibitor which is used in the treatment of Parkinson’s disease. It is postulated that even higher selectivity for the MAO-B isoform may be obtained when rasagiline is substituted on C4 of the indan phenyl ring. It is hypothesised that the entrance and substrate cavities will fuse as the substituent occupies the entrance cavity and rasagiline the substrate cavity of MAO-B. Inhibitors that display this cavity-spanning mode of inhibition generally do not inhibit MAO-A, which would make C4 substituted rasagiline analogues highly specific for MAO-B. Such compounds would possess a low risk of the cheese reaction and serotonin syndrome. Since 1-indanone is similar in structure to rasagiline, this theory was investigated by substitution of 1-indanone on the C4 position with relatively large substituents. The synthesised 1-indanone derivatives were reduced to the corresponding 1-indanol derivatives in order to compare MAO inhibition potencies of the carbonyl and alcohol derivatives.
The structures of the synthesised 1-indanone and 1-indanol derivatives were elucidated by nuclear magnetic resonance (NMR) and mass spectrometry (MS). Purity of the compounds were estimated by high pressure liquid chromatography (HPLC). All compounds were evaluated as inhibitors of human MAO-A and MAO-B by recording their IC50 values. 6-(4- Chlorobenzyloxy)-1-indanone exhibited the highest MAO-B inhibition potency with an IC50 value of 0.000076 μM. This study concluded that 1-indanone derivatives are generally more potent inhibitors of human MAO-B than the corresponding 1-indanol derivatives. The most potent 1-indanol derivative, 5-(4-chlorobenzyloxy)-1-indanol, exhibited an IC50 value of 0.007 μM for the inhibition of human MAO-B.
Reversibility studies were conducted with the selected 1-indanol derivative that exhibited the highest MAO-B inhibition potency. Previous studies have already shown that 1-indanone derivatives are reversible MAO inhibitors. In addition, the reversibility of MAO-A inhibition of 4-hydroxy-1-indanone (IC50 = 2.15 μM) was also examined since this compound displayed the most potent MAO-A inhibition of the series. The results obtained showed that both compounds are reversible inhibitors of MAO
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