Graduation Date

Summer 8-11-2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

Corey Hopkins, PhD

Second Advisor

Jonathan L. Vennerstrom, PhD

Third Advisor

Paul Trippier, PhD

Fourth Advisor

Amarnath Natarajan, PhD

Abstract

Dopamine (DA) is an important neurotransmitter for the regulation and long-term function of the central nervous system (CNS). DA binds to Dopamine Receptors (DR) to stimulate or inhibit adenyl cyclase production to further elicit a pharmacological response. DRs were cloned, and it was determined that there are two families separated by their function and five total subtypes distinguished by their amino acid structure. The Dopamine 4 receptor (D4R) is the second least studied subtype but has high expression in the frontal cortex, amygdala, hippocampus, hypothalamus, globus pallidus, substantia nigra pars reticula, and thalamus. Dopamine signaling and transmission, especially in the nigrostriatal pathway, play a significant role in controlling movement and learning new motor skills. Malfunction in signaling and degradation of neurons lead to motor complications and disorders such as Parkinson’s Disease (PD). The gold standard treatment of PD is dopamine replacement therapy with L-DOPA. The therapeutic benefit of L-DOPA depends on the amount and stability of the dopaminergic neurons. Long-term treatment with L-DOPA leads to unwanted side effects that could be more debilitating than PD. Other treatments, such as Dopamine 2 receptor agonists, could delay L-DOPA treatment but lead to adverse effects such as psychosis. Studies have been done to treat L-DOPA-induced dyskinesias (LID), but very few drugs have shown a significant benefit in a clinical setting. Previously, our laboratory identified a series of morpholine compounds that alleviated LID in mouse and non-human primate models but did not have good metabolic stability. Our focus was to develop potent compounds with high selectivity over the other DR subtypes and other CNS receptors and more stable compounds.

The Sigma-1 receptor (S1R) is a CNS receptor found on the endoplasmic reticulum in cells. The mechanism of action for S1R has not been fully elucidated, but some studies have proven its role in Alzheimer’s Disease, PD, pain, and cancer. Chapter 2 discusses the discovery of S1R modulators from our previous D4R structure-activity relationship studies. Our studies showed a pattern, and we are working on developing potent, selective, and metabolically stable compounds. Determining whether these compounds are antagonists or agonists is being studied currently and the results will direct our future studies' paths.

Chapter 3 includes work in Claudin-1 inhibitors for the treatment of colorectal cancer. The initial inhibitor, determined by in silico screening, showed anti-tumorigenic potential but was not metabolically stable. A SAR study was conducted to find a more stable compound, showing significant activity in inhibiting claudin-1. This chapter also includes work from a project focused on transient receptor potential (TRP) channel-canonical 5 (TRPC5). It was shown that TRPC5 plays a role in chronic kidney disease. SAR studies focused on improving potency and pharmacokinetic liabilities.

Comments

2023 Copyright, the authors

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