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
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