Alcoholism is a prevalent multifactorial disease with both genetic and environmental components. Monoamine oxidase (MAO) has been proposed as a susceptibility marker for familial alcoholism but consistent evidence of either specific MAO variants in alcoholics or allelic segregation in at-risk families has not been presented. Two structural genes on the X chromosome encode two forms of the enzyme, MAO-A and MAO-B. Kinetic constants for platelet MAO-B and restriction fragment length polymorphisms for MAO-A were determined in alcoholics with multigenerational family histories of alcoholism, high risk relatives of familial alcoholics and low risk controls with no family history of alcoholism. Mean elevated levels of MAO-B deamination were observed in alcoholics and high risk individuals. Alcoholic and high risk individuals did not differ from non-alcoholics with respect to MAO-B tryptamine affinity or MAO-A polymorphisms. Significant non-genetic factors influence MAO-B activity. MAO variants are unlikely to define a genetic predisposition to alcoholism.

This document only includes an excerpt of the corresponding thesis or dissertation. To request a digital scan of the full text, please contact the Ruth Lilly Medical Library's Interlibrary Loan Department (rlmlill@iu.edu).

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Magister Pharmaceuticae - MPharm / Alzheimer's disease is a progressive neurodegenerative disease characterised by low acetylcholine (ACh) levels in the hippocampus and cortex of the brain, causing symptoms like progressive memory loss, decline in language skills and other cognitive impairments to occur. The hallmarks of AD include the presence of extracellular insoluble amyloid beta plaques, intracellular neurofibrillary tangles, and the decrease in ACh concentration. The pathophysiology of AD is not well understood, however, acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and monoamine oxidases (MAO) are conspicuous role players in AD pathogenesis. Based on the cholinergic hypothesis, the AChE inhibitor donepezil was developed and has been used effectively clinically in the management of AD, with minimal side effects. Studies regarding the binding interactions of donepezil with AChE has shown that the benzyl-piperidine moiety of this compound shows substantial binding interactions at the CAS site of AChE where it blocks AChE activity. Coumarin is a compound of natural source that has shown some MAO inhibitory activity. Further studies done to clarify the potential of coumarin as a drug against AD has shown that coumarin has the capacity to bind at the PAS site of AChE, thus giving it the potential to prevent AChE induced amyloid plaque formation. Due to the multifactorial nature of AD, the drugs in the market show limited therapeutic benefits and are mainly for symptomatic relief. In order to address this limitation in AD treatment, researchers are exploring the possibility of designing a multi-target-directed-ligand (MTDL). The aim of this study was to synthesise a series of compounds out of pharmacophoric groups of donepezil and coumarin that will be able to inhibit both cholinesterases and MAO B. Four series of 5 compounds per series were synthesised. The first series of compounds consisted of the coumarin moiety to which a 1,4-dibromo benzene moiety was attached. The second series represented the coumarin moiety to which a piperidine (donepezil moiety shown to confer cholinesterase inhibitory property) was attached. The third series represented the coumarin moiety to which bromobenzyl-piperazine was attached and in the last series were compounds similar in structure to series 1 with an unsubstituted benzyl moiety as opposed to the dibromobenzyl moiety. Prior to the synthesis, molecular modelling was conducted in order to have an idea of the binding capacity of the compounds to MAO A and B and cholinesterases. In vitro biological evaluation of the compounds was done and used to determine the IC₅₀ values of the compounds. Nineteen compounds were synthesised and purified successfully as shown by their NMR, MS and IR spectra. The compounds to which dual inhibitory activity was conferred were those in series 2 and 3, of which series 2 showed the best overall inhibitory activity with IC₅₀ values within the low μM range. The compound with the best overall activity was Cp 9. Molecular modelling of Cp 9 showed that the coumarin core was located in the PAS region of AChE while the benzyl-piperidine moiety was situated in the CAS region of the enzyme. This compound orientation demonstrates the potential of Cp 9 to inhibit AChE induced amyloid beta plaque formation. Cp 9 showed no inhibitory activity towards MAO A, but showed good inhibitory activity towards MAO B with an IC₅₀ value of 0.30 μM. Its inhibitory activity towards cholinesterases also fell within the low μM range (AChE IC50 = 9.1 μM and BuChE IC₅₀ = 5.9 μM). From the results, it can be concluded that Cp 9 was able to inhibit both cholinesterase and MAO B catalytic activities at low μM concentrations. This thus means that our novel compound will not only increase ACh levels in the brain thus improving cognitive activity, but it will also have neuroprotective effect from its MAO B inhibitory property and also potentially slow down amyloid plaque formation due to AChE activity. / National Research Foundation (NRF)

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Thesis (doctoral)--Umeå Universitet, 1986. / Added t.p. with thesis statement inserted. Includes bibliographical references.

Thesis (doctoral)--Umeå Universitet, 1986. / Added t.p. with thesis statement inserted. Includes bibliographical references.

Thesis (Ph. D.)--University of Texas at Austin, 1998. / Vita. Includes bibliographical references (leaves 197-208). Available also in a digital version from Dissertation Abstracts.

BACKGROUND AND RATIONALE Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disorder affecting the central nervous system, primarily, the substantia nigra. It is characterized by loss of dopaminergic neurons in the nigro-striatal pathway, and ultimately patients with Parkinson’s disease may lose up to 80% of their dopamine-producing cells in the brain. Symptoms include bradykinesia, muscle rigidity, resting tremor and impaired postural balance. Symptomatic relief is obtained by using levodopa and various adjunct therapy including dopamine agonists, catechol-O-methyltransferase inhibitors and monoamine oxidase B inhibitors. Levodopa is used as the gold-standard for treatment of this disease. It effectively controls motor symptoms, however, motor complications that impair the quality of life develop with continued levodopa use. No treatments currently available can halt disease progression, therefore novel drugs that can slow down or stop disease progression are urgently required. The monoamine oxidase (MAO) A and B enzymes are flavoenzymes that play an important role in the oxidative degradation of amine neurotransmitters such as dopamine, serotonin and epinephrine. Early attempts to block dopamine metabolism in the brain using nonselective MAO inhibitors was effective but led to side effects such as hypertensive crisis, thus they lost favor. The MAO-B enzyme is of particular importance in Parkinson’s disease because it is more active than MAO-A in the basal ganglia, and is thus primarily responsible for the catabolism of dopamine in the brain. Selegiline and rasagiline, both irreversible, selective MAO-B inhibitors have proven efficacy in symptomatic treatment of Parkinson’s disease, but due to the irreversible nature of their binding, it can take several weeks after treatment termination for the enzyme to recover. Use of reversible inhibitors such as lazabemide and safinamide do not have this disadvantage, and have safer side effect profiles. Unfortunately, clinical trials for lazabemide use in Parkinson’s disease have been discontinued. Therefore, due to the lack of disease modifying agents for Parkinson’s disease, as well as safety concerns of current PD therapy, an urgent need exists for novel, safe and efficient MAO inhibitors. Current research is thus aimed at designing selective or non-selective reversible inhibitors that bind competitively to the enzyme. The MAO inhibitory potential of chromone derivatives has been illustrated previously. Evaluation of C6- and C7-alkyloxy substituted chromones, for example revealed that these compounds were potent, selective and reversible MAO-B inhibitors. It has further been shown that chromone 3-carboxylic acid is a potent selective, irreversible MAO-B inhibitor. Phenylcarboxamide substitution in position 3 of chromone 3-carboxylic acid also results in potent, selective MAO-B inhibitory activity. Therefore, further evaluation of the effect of substitution with flexible side chains in the 3-position to evaluate MAO-B inhibition is of importance. The chromone ring system is thus a privileged scaffold for the design of inhibitors that are selective for MAO-B and has the additional advantages of generally exhibiting low mammalian toxicity and ease of synthesis. AIM The aim of this study was to design, synthesize and evaluate novel chromone derivatives as inhibitors of monoamine oxidase. RESULTS Design and Synthesis 3-Aminomethylene-2,4-chromandiones and ester chromone derivatives were synthesized by coupling several aromatic and aliphatic amines and alcohols, to chromone 3-carboxylic acid, in the presence of CDI (carbonyldiimidazole). 15 Compounds were successfully synthesized and characterized by using NMR and IR spectroscopy, as well as mass spectrometry. X-ray crystallography was used to obtain a crystal structure for the 3-aminomethylene-2,4- chromandione derivative, 46, in a bid to verify the structures of the synthesized compounds. Melting points of all compounds were determined, and the purity determined using HPLC techniques. MAO inhibition studies A fluorometric assay was employed using kynuramine as substrate, to determine the IC50 (50% inhibition concentration) values and SI (selectivity index) of the synthesized compounds. Generally, the esters exhibited weak MAO-A and MAO-B inhibition, while the 3- aminomethylene-2,4-chromandione derivatives showed promise as selective MAO-B inhibitors, with IC50 values in the micromolar range. Compound 38, 3- [(benzylamino)methylidene]-3,4-dihydro-2H-1-benzopyran-2,4-dione, was the most potent MAO-B inhibitor with an IC50 value of 0.638 μM and a SI of 122 for MAO-B inhibition. Interesting trends were revealed through analysis of the structure activity relationships, for example, for the 3-aminomethylene-2,4-chromandione derivatives, the presence of a chlorine moiety in the side chains of the compounds resulted in a decrease of MAO-B inhibition activity. Chain elongation further also resulted in weakening the MAO-B inhibition activity, while chain elongation in the ester derivatives led to a slight increase in MAO-B inhibition activity. Reversibility studies The reversibility of binding of the most potent compound in the 3-aminomethylene-2,4- chromandione series, 38, was evaluated. None of the synthesized inhibitors were potent MAO-A inhibitors, therefore reversibility of MAO-A inhibition was not examined. Recovery of enzyme activity was determined after dialysis of the enzyme-inhibitor complexes. Analysis of the kinetic data obtained showed that MAO-B catalytic activity was recovered to 115% of the control value. This suggests that compound 38 is a reversible inhibitor of MAO-B. Mode of inhibition A set of Lineweaver-Burk plots were constructed to determine mode of inhibition of compound 38. The results show linear lines that intersect at a single point just to the left on the y-axis. This indicates that compound 38 interacts competitively with the MAO-B enzyme. In conclusion, chromone derivatives were synthesized and evaluated as inhibitors of MAO. Compound 38 was the most potent MAO-B inhibitor with an IC50 value of 0.638 μM. The effect of chain elongation and introduction of flexible substituents in position 3 of the chromone 3-carboxylic acid nucleus was explored and the results showed that 3- aminomethylene-2,4-chromandione substitution is preferable over ester substitution. / MSc (Pharmaceutical Chemistry), North-West University, Potchefstroom Campus, 2015