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Access Type
WSU Access
Date of Award
January 2024
Degree Type
Dissertation
Degree Name
Ph.D.
Department
Pharmaceutical Sciences
First Advisor
Aloke K. Dutta
Abstract
Parkinson’s Disease (PD) and Parkinson’s Disease with Dementia (PDD) are age-related disorders marked by the degeneration of the nigrostriatal dopaminergic system, and the accumulation of α-synuclein (αSN) into Lewy Bodies and Lewy Neurites. The loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) produces the cardinal motor symptoms and cognitive decline leading to dementia. While the etiology is not well established, the nature of the disease is complex and multifunctional. Several factors have been implicated in the disease process such as protein aggregation, oxidative stress, and loss of mitochondrial integrity leading to neuronal cell death. However, therapies clinically approved for PD are symptomatic in nature and do not target these factors listed above. Our goal is to design and develop multifunctional dopamine agonists to not only relieve the symptoms of motor dysfunction in PD but also to exert neuroprotective effects via modulating aggregation of αSyn protein to alter the progression of these diseases, an urgent unmet need. This multifunctional template, excluding the dopamine agonist, will be further developed to target hallmarks of Alzheimer’s disease (AD).
AD is an age-related, neurodegenerative disease that is the leading cause of dementia worldwide. This disease is hallmarked by the degeneration of the cholinergic system and accumulation of senile plaques (amyloid-β) and neurofibrillary tangles (NFT’s) leading to cognitive decline. Similar to PD, the etiology of AD is not well-known, but there are several factors implicated in the disease process: Aβ and tau aggregation, oxidative stress, and cholinergic depletion. While current clinical treatments for AD include acetylcholinesterase inhibitors and an NMDA agonist, to enhance cognition they do not slow or modify the disease pathology. Given the complexity of AD, taking a novel approach to target multiple factors could prove useful. Our goal is to utilize the multifunctional template from previous work on D-520. Realizing contribution of biphenyl catechol moiety towards inhibition of amyloidogenic proteins, we seek to truncate the dopamine agonist moiety to develop molecules exclusively targeting amyloid beta peptide and tau protein whose toxicities are implicated in the pathogenesis of AD. Structure-activity relationship studies were explored in this dissertation to find potent leads that encompass the multi-functional dual activities. Furthermore, lead molecules were developed into pro-drugs to enhance pharmacokinetic properties to increase the concentration of the parent molecule in the brain.
Recommended Citation
Armstrong, Christopher, "Synthesis Of Multifunctional Ligands For The Treatment Of Parkinson’s And Alzheimer's Disease" (2024). Wayne State University Dissertations. 4014.
https://digitalcommons.wayne.edu/oa_dissertations/4014
