Access Type

Open Access Dissertation

Date of Award

January 2013

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Pharmaceutical Sciences

First Advisor

Aloke K. Dutta

Abstract

Parkinson¡¯s disease (PD) is a progressive, neurodegenerative disorder that arises primarily through the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc), resulting in a diminished level of the neurotransmitter dopamine in the nigrostriatal pathway and ensuing loss of motor function. Common symptoms of PD include resting tremor, muscular rigidity, bradykinesia (slowness and decreased amplitude of movement), along with postural instability and cognitive psychiatric complications. PD affects 1% of the population ¡Ý 65 and is the second most prevalent neurodegenerative disorder next to Alzheimer¡¯s disease (AD). Although the etiology of PD is not yet clear and may be multifactorial, oxidative stress and mitochondrial dysfunction are thought to play a central role in the pathology of the disease. L-dopa, the biosynthetic precursor to DA, is the gold-standard treatment option for PD. Although initially beneficial in reducing motor symptoms, chronic L-dopa treatment causes pharmaco resistant involuntary movements, ¡°on¡± and ¡°off¡± phases and may even exacerbate the progression of PD. It has become increasingly evident that for a complex disease such as PD, a drug aimed at one target site will only partially address the therapeutic need of the disease. Thus, it is hypothesized that multi-functional drugs, having multiple pharmacological activities, will be more effective in treating PD. Our approach in developing such agents involves alleviating symptoms of the disease, along with preventing or halting the neurodegeneration process. To this end, we have utilized our hybrid molecular template to design novel, D3-preferring agonists, with a range of selectivity for D3 receptor, while also incorporating antioxidant moieties to provide antioxidant capacity to the molecule. In this dissertation, we investigate the potential of our D3-preferring agonists to not only alleviate motor symptoms of PD, but also to modify the progression of disease.

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