Access Type

Open Access Dissertation

Date of Award

January 2017

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Pharmaceutical Sciences

First Advisor

Aloke K. Dutta

Abstract

Parkinson’s disease (PD) is an age-related neurodegenerative disease, which is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of intraneuronal proteinaceous deposits named Lewy bodies (LBs) or Lewy neurites (LNs). A broad spectrum of motor and non-motor symptoms has been observed in PD, with bradykinesia, resting tremor, rigidity, and postural instability as its key clinical features. Although the etiology of PD is still not well-understood, multiple pathological factors including oxidative stress, mitochondrial dysfunction, α-synuclein (αSN) protein aggregation, as well as genetic and environmental aspects are strongly implicated in the disease progression. The present treatments available for PD generally fall into four major categories, namely levodopa/carbidopa, monoamine oxidase B (MAO-B) inhibitors, catechol-O-methyl transferase (COMT) inhibitors, and dopamine agonists. However, these current clinical treatments are only able to provide symptomatic relief and fail to delay the disease progression. Furthermore, the long-term use of levodopa leads to motor complications including the development of dyskinesia. Thus, there is still a great unmet need for effective treatment of PD which should involve disease modification. Due to the complexity observed in the disease pathogenesis, treatments that incorporates the pathogenic factors involved in PD might offer an advantage in combating the disease by modifying the disease progression. The hypothesis of this project is that the incorporation of dopamine D2/D3 agonistic binding component to accessory moieties targeting either αSN aggregation or MAO-B enzyme may lead to multifunctional drugs with a potential to provide both symptom-reliving and disease-modifying effects as a promising approach for new generation PD treatment.

In this dissertation, two library of compounds have been developed based on the previously established hybrid structure approach, and the initial structure-activity relationship (SAR) study has been perused to identify possible lead compounds through in vitro and in vivo evaluations. The first main objective is to design and develop a series of novel dopamine D2/D3 receptor agonists that can potentially modulate α-synuclein (αSN) aggregation by combining the dihydroxy or hydroxy-methoxy component with D2/D3 agonist fragment through various linkers according to the hybrid molecular template. Based on the results of in vitro receptor assays, compounds (−)-8a (D-593), (−)-20 (D-618), (−)-14 (D-644), and (−)-49 (D-670) were selected and further evaluated to determine their potential αSN aggregation modulatory properties and neuroprotective effect. Subsequently, compound (−)-8a (D-593) was identified as a lead compound by using a well-established Parkinson’s disease (PD) animal model. The second main objective is to design and synthesize a series of novel dopamine D2/D3 receptor agonists that may potentially inhibit monoamine oxidase B (MAO-B) activity by introducing the propargyl group into the hybrid molecular template. An initial SAR study was conducted based on the generated compound library through in vitro receptor assays and enzymatic studies which led to the identification of compounds (−)-62b (D-629) and (−)-76 (D-614) as potential candidates. Moreover, in vitro neuroprotection models and a PD animal model were used to further evaluate them, and (−)-76 (D-614) was identified as the lead compound that requires further modification.

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