The advancement of medicine around the world is happening at a rapid speed. There is not a day that one does not hear about a disease being cured or a wonder-drug being developed. Medicine has always been a field that treated a sick patient to bring that person back to “normal” function, which could be said to be the state he or she was in before acquiring the disease in question. However, due to scientific breakthroughs humanity is in a position that historically it has never been before. A place where a person can increase their mental and physical performance using pharmaceuticals to a level where genetics and upbringing alone would not have allowed. Pharmaceuticals have been created which can do for the brain what has been done for the body. These drugs provide an avenue in which a person’s cognitive functions can be increased beyond what was otherwise possible. The ethical and legal dilemmas posed by prescribing or allowing people to use nootropics is hotly debated. Greely, a leading figure in the bioethical debate, in connection with nootropics, has stated that the ethical concerns comprise three main aspects: safety, fairness and coercion., It is clear that these three aspects cover a wide ambit. The arguments for and against nootropics will not merely be rehashed but rather placed into the South African context to ascertain how best to provide for the ethical concerns relevant to South Africa. The ethics of nootropic use will be examined through the lens of the Beuchamp Childress model which determines ethical problems using the principles of autonomy, justice, beneficence and non-maleficence. The aim and contribution of this thesis will be to build a legal framework for the use of nootropics in South Africa, to create this one must ascertain what the current legal position is. Law is built from precedent in context of case law and legislation. The current law will be examined to see what can be used, what may need to be discarded and what would need to be added. A layered approach is used to determine what the legal position in South Africa currently is. A layered approach looks at the constitution and proceeds to legislation, case law, and legal articles and books. A major aspect around the use of nootropics will be informed consent and how it relates to the use of nootropics especially with regards to adolescents i.e. under 18 years of age. This thesis follows an MPhil in Medical Law and Ethics which outlined the doctrine of informed consent in South Africa and thus allows for the application of this doctrine to a pressing issue in South African society. / Thesis (PhD)--University of Pretoria, 2019. / Public Law / PhD / Unrestricted

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Schizophrenia is a neuropsychiatric disorder lying at the extreme of a spectrum of disorders that possibly share a common abnormality in neural connectivity. Efforts to reverse the core cognitive manifestations of schizophrenia using drug treatments have so far been unsuccessful. This thesis investigates the cognitive abnormalities and their electrophysiological correlates across the schizophrenia spectrum in order to identify and validate biomarkers for proof of concept studies of cognitive enhancers. Such studies in milder disorders of the schizophrenia spectrum such as schizotypal personality trait may be a crucial method in identifying new effective compounds, as reviewed in Chapter 3, and tested in Chapter 4. The latter features the results of a large three-centre study which probed the sensitivity of several neuropsychological measures to the schizotypy phenotype, as well as to the effects of amisulpride, risperidone and nicotine. Schizotypal volunteers showed impaired performance only on the more difficult tasks. The most consistent pharmacological finding was that amisulpride tended to improve performance in the high schizotypy group but to impair it in the average schizotypy controls. One interpretation is that the ability of low dose amisulpride to enhance dopamine function in frontal cortex reversed an impairment of dopamine function present in the high schizotypes which is thought to occur in schizophrenia. Chapter 5 explored the methodological question of whether low or average schizotypy individuals should be used as controls in cognitive comparisons versus high schizotypy. The results suggest that low schizotypes have the most intact cognitive performance and are therefore the control group of choice. Chapters 6, 7 and 8 tested the hypothesis that cognitive deficits are part of a larger information processing abnormality in the schizophrenia spectrum. In accordance, both high schizotypy and schizophrenia patients exhibited reduced amplitude of an early visual evoked potential P1 (Chapters 6 and 8, respectively) and disruptions of the underlying evoked neural oscillations (Chapters 7 and 8). The pattern of abnormalities suggested an inefficient top-down modulation of perception in the schizophrenia spectrum. These data argue that cognitive abnormalities and their electrophysiological correlate may be sensitive biomarkers of the core dysconnectivity deficit in schizophrenia. This thesis supports their use in proof of concept studies to foster the development of cognitive enhancers.

The need for alternative cognitive enhancers has risen due to the fact that clinical trial results of the drugs currently approved for treating these disorders have not been satisfactory. IRAP has become a possible drug target for treating cognitive impairment brought about by Alzheimer’s disease, head trauma or cerebral ischemia, among others. This came after the revelation that Angiotensin IV enhances memory and learning. Angiotensin IV, the endogenous ligand of IRAP has been structurally modified with the aim of producing potent IRAP inhibitors. However, the peptidic nature of these inhibitors restricts their use; they are not likely to cross the blood brain barrier. Other strategies for generating IRAP inhibitors have been through structure-based design and receptor based virtual screening. These drug-like molecules have exhibited positive results in animal studies. IRAP inhibitors have been identified via a HTS of 10500 low-molecular weight compounds to give the hit based on a spirooxindole dihydroquinazolinone scaffold, with an IC50 value of 1.5 µM. In this project, some analogues to this hit compound have successfully been synthesized using a known method, whereas others have been synthesized after additional method development. The application of the developed method was found to be limited, because poor yield was obtained when a compound with an electron withdrawing substituent on the aniline was synthesized. As a result of this, modification of this method may be required or new methods may have to be developed to synthesize these types of analogues. Inhibition capability of 5 new spirooxindole dihydroquinazolinones was tested through a biochemical assay. Compound 6e emerged as the most potent inhibitor in the series, with an IC50 value of 0.2 µM. This compound will now serve as a lead compound and should be used as a starting point for future optimization in order to generate more potent IRAP inhibitors.