Monoamine oxidase inhibition properties of quinolinone analogues

Abstract

Parkinson's disease (PD) is an age-related neurodegenerative disorder characterised by selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the brain. This leads to the loss of dopamine from the striatum, which is responsible for the motor symptoms of PD. Monoamine oxidase (MAO) plays an important role in the neurodegenerative processes and therapy of PD since dopamine is oxidised by MAO in the basal ganglia. Inhibitors, of the MAO-B isoform conserve the depleted supply of dopamine and are thus used in the therapy of PD. MAO-B inhibitors may also enhance the therapeutic efficacy of L-dopa, the metabolic precursor of dopamine, by enhancing dopamine levels derived from administered L-dopa. In this study, three chemical classes were synthesised and evaluated as potential recombinant human MAO-A and MAO-B inhibitors. These include (1) C6- and C7-substituted 3,4- dihydro-2(1H)-quinolinones, (2) 2-phenoxyethoxy-substituted tetralones and (3) Npropargylamine- 2-aminotetralin (2-PAT). The quinolinone and tetralone derivatives are structurally related to chemical classes that have been reported to inhibit the MAO enzymes, including a-tetralone, 1-indanone and 3-coumaranone derivatives. 2-PAT is structurally similar to rasagiline, an irreversible MAO-B inhibitor currently used in clinic. C6- and C7-substituted 3,4-dihydro-2(1H)-quinolinone and 2-phenoxyethoxy tetralone derivatives were synthesised by reacting 6- or 7-hydroxy-3,4-dihydro-2(1H)-quinolinone and 6- or 7-hydroxytetralone, respectively, with an appropriately substituted alkyl bromide in the presence of base. 2-PAT was synthesised in low yield by dehydrating ~-tetralone and propargylamine (commercially available) in the presence of sodium cyanoborohydride (NaCNBH4). To evaluate the MAO inhibitory properties (IC50 values) of the synthesised derivatives the recombinant human MAO-A and MAO-B enzymes were used. The reversibility of inhibition of selected derivatives was examined by employing dialysis, while the mode of MAO inhibition was determined by constructing Lineweaver-Burk plots. To determine possible binding modes and key interactions of selected inhibitors with the MAO enzymes, the inhibitors were docked into the MAO active sites. The results document that the 3,4-dihydro-2(1H)-quinolinone derivatives are highly potent and selective MAO-B inhibitors with the most potent inhibitor displaying an IC50 value of 0.0014 μM. Based on dialysis experiments it was concluded that a selected quinolinone derivative is a reversible MAO-B inhibitor. The Lineweaver-Burk plots constructed for the inhibition of MAO-B by the selected quinolinone derivative were linear and intersected on the y-axis. These data indicated that this compound is a competitive MAO-B inhibitor with a Ki value of 2.8 nM. The results further document that 7-(2-phenoxyethoxy)-3,4-dihydronaphthalen-2(1H)-one from the second series is a highly potent MAO-B inhibitor with an IC50 value of 0.033 μM. Based on dialysis experiments it was concluded that this ~-tetralone derivative is a reversible and competitive MAO-B inhibitor. An analysis of the Lineweaver-Burk plots indicated that this compound inhibit MAO-B with a Ki value of 0.128 μM. This is the first report of the MAO inhibition properties of a ~-tetralone. Finally, 2-PAT was found to be a reversible MAO-A (IC5o= 0.721μM) inhibitor, while acting as an inactivator of MAO-B (IC50 = 14.6 μM). 2-PAT is also approximately fivefold more potent than toloxatone (IC50 = 3.92 μM), a clinically used antidepressant and reversible MAO-A inhibitor. It may thus be concluded that the synthesised compounds are promising potent MAO-B inhibitors, and thus leads for the design of therapeutic agents for PD