Synthesis and evaluation of nitrocatechol derivatives of chalcone as inhibitors of monoamine oxidase and catechol-O-methyltransferase
Abstract
Parkinson’s disease is a progressive neurological movement disorder that worsens with age. Parkinson’s disease is still the most frequent neurodegenerative disorder after Alzheimer’s disease. There is no known cause of Parkinson’s disease, but in some cases there may be
non-genetic or genetic risk factors. The non-genetic risk factors include environmental factors and exposure to organic solvents, carbon monoxide, carbon disulphide and pesticides. An example of a compound that induces a Parkinsonian syndrome in humans and animals is the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which selectively damages the dopaminergic cells in the substantia nigra. Genetic mutations in genes such as DJ-1, PINK1 and LRRK-2 can cause familial Parkinson’s disease. The main pathological features of Parkinson’s disease are the degeneration and the loss of the dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of “Lewy-bodies’ in the brain. The SNpc forms part of the basal ganglia which coordinates muscle
movement through the direct and indirect pathways, and connects with the motor cortex. The substantia nigra can be divided into two regions. The first region is the pars reticulata, which receives signals from the striatum, and send signals to the thalamus via the neurotransmitter, GABA (gamma-aminobutyric acid). The motor cortex receives these signals from the thalamus that initiates voluntary muscle movement. The second region is the pars compacta, which is the area that is mostly affected in Parkinson’s disease. The pars compacta send signals to the striatum via the neurotransmitter, dopamine, forming the nigrostriatal pathway that stimulates the
cerebral cortex and initiates movement. When the SNpc neurons die, muscle movement cannot be initiated via the direct pathway, and a decrease in movement in the indirect pathway cannot be reduced, thus resulting in slow muscle movement. The two isoenzymes of monoamine oxidase (MAO) are MAO-A and MAO-B. They are both flavoenzymes which are responsible for the catalysis of the oxidative deamination of biogenic amines and amine neurotransmitters such as dopamine, serotonin and noradrenaline. The MAO
enzyme metabolises dopamine after it has been produced in the brain and thus reduces binding of dopamine to the dopamine receptor. MAO inhibitors will bind to MAO and reduce the central metabolism of dopamine. With more dopamine available to bind to dopamine receptors in the brain, dopaminergic neurotransmission is enhanced. MAO inhibitors thus reduce dopamine depletion in the striatum of the brain. MAO-B activity in the brain increases with age and the activity is furthermore higher in the brain tissue of Parkinson’s disease patients, which further depletes central dopamine. The main clinical features of Parkinson’s disease include resting tremor, rigidity, postural instability and bradykinesia. The treatment of these motor symptoms are mainly based on the re-establishment of striatal dopaminergic neurotransmission, which may be achieved by increasing the dopamine supply through levodopa administration. Levodopa is still considered the most effective treatment for Parkinson’s disease. Levodopa can be administered orally and enters
the systemic circulation. In the periphery, levodopa will be metabolised to dopamine by the enzyme aromatic L-amino acid decarboxylase (AADC), while catechol-O-methyltransferase (COMT) will metabolise dopamine to yield to 3-O-methyldopa. These metabolic reactions further reduce the amount of levodopa available to cross the blood-brain barrier. AADC inhibitors (carbidopa and benserazide), and COMT inhibitors (tolcapone and entacapone) will block the peripheral action of AADC and COMT, thereby reducing the conversion of levodopa to dopamine. A larger fraction of levodopa is thus available to cross the blood-brain barrier. In the central nervous system, levodopa is taken up by the nigrostriatal dopaminergic neurons, and metabolised by AADC to dopamine. MAO-B inhibitors (e.g. selegiline) and COMT inhibitors (e.g. tolcapone) prevent dopamine metabolism in the brain. The overall effect of these inhibitors is to increase the amount of dopamine available to bind to dopamine receptors in the corpus striatum, thus increasing motor activity. The current treatments that are available for Parkinson’s disease focus mostly on the management of symptoms, while there are only a few drugs available on the market for the treatment of Parkinson’s disease. New treatment strategies need to be developed, and this dissertation will attempt to contribute by synthesising novel compounds that may inhibit both MAO and COMT. In the current study we synthesised three novel nitrocatechol derivatives of chalcone as well as their corresponding pyrazoline derivatives, and investigated their MAO and COMT inhibition potencies. The inhibition potencies were expressed as IC50 values, and the results indicated that both the chalcone and pyrazoline derivatives are high potency inhibitors of rat liver COMT. The pyrazoline derivatives (IC50 = 0.048-0.079 μM) are more potent COMT inhibitors than the chalcones (IC50 = 0.175-0.240 μM). The most potent COMT inhibitor among the pyrazoline
derivatives is 4-[1-acetyl-3-(3,4-dihydroxy-5-nitrophenyl)-4,5-dihydro-1H-pyrazol-5- yl]benzonitrile, which possesses an IC50 value of 0.048 μM. Furthermore, the six newly synthesised compounds are more potent COMT inhibitors compared to the reference COMT
inhibitors, tolcapone (IC50 = 0.26 μM) and entacapone (IC50 = 0.25 μM). The chalcone and pyrazoline derivatives were also evaluated as potential inhibitors of MAO-A and MAO-B with the aim of discovering compounds with dual inhibitory activity towards MAO and
COMT. Unfortunately, the chalcone and pyrazoline derivatives that were investigated in this study were weak inhibitors for both MAO-A and MAO-B. Even though the compounds showed weak inhibition for MAO, the pyrazoline derivatives should be further studied for their potent COMT inhibition activities, as they may represent potentially clinically valuable inhibitors of COMT
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