Schizophrenia is a severe mental disorder that can manifest in various ways and is often characterized by the appearance of positive symptoms (hallucinations, delusions), negative symptoms (social and attention impairment) and cognitive dysfunction (thought disorders, memory and executive function impairments). Traditional treatment methodologies involve blocking the dopamine receptor by binding to the same site as dopamine. These treatments are largely inadequate and lead to an array of adverse side effects. Side effects include weight gain, diabetes, and movement disorders; which critically limit the therapeutic value of antipsychotic drug treatment. Limited symptom control and severe adverse effects have led to poor drug adherence and a deprived quality of life for patients suffering from schizophrenia. The complex etiology of schizophrenia combined with a lack of effective translational models and tests to represent and assess the illness have hindered drug development. Evidently, there is a strong demand for a new generation of pharmaceuticals and an improved translational pipeline for the treatment of schizophrenia. The collection of studies presented here contribute to the advancement of translational tools for drug discovery, the establishment of pre-clinical models to embody the various symptoms, and the development of a novel drug candidate for schizophrenia. Allosteric modulation of G-protein coupled receptors is evolving as a new wave of therapy with promising implications for various CNS disorders. Allosteric compounds regulate binding without blocking the receptor. PAOPA, a dopamine D2 receptor allosteric modulator, prevents and treats schizophrenia-like symptoms in pre-clinical animal models of schizophrenia with no apparent adverse effects. The studies outlined in this thesis further categorize PAOPA as a novel therapeutic candidate for schizophrenia. Moreover, the findings presented here provide further insight into the potential therapeutic mechanism of action of PAOPA and set the foundation for the development of a new generation of antipsychotic drugs. These studies constitute an innovative approach to expanding research in the field of drug development for schizophrenia. / Thesis / Doctor of Philosophy (PhD)
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/21965 |
| Date | January 2017 |
| Creators | Daya, Ritesh P. |
| Contributors | Mishra, Ram K., Neuroscience |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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