ORCID ID
Graduation Date
Spring 5-7-2026
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Programs
Pharmaceutical Sciences
First Advisor
Dr. Corey Hopkins
Abstract
Alzheimer’s disease (AD), Parkinson’s disease (PD), and colorectal cancer (CRC) remain significant clinical challenges requiring improved therapeutic strategies. This dissertation describes the design, synthesis, and pharmacological evaluation of structurally diverse small-molecule scaffolds targeting the sigma-1 receptor (S1R) for symptomatic modulation in AD, the dopamine D4 receptor (D4R) for management of L-DOPA–induced dyskinesia in PD, and claudin-1 for targeted intervention in CRC. Fused azabicyclic scaffolds were developed as S1R modulators, and systematic structure–activity relationship (SAR) studies identified key structural features governing receptor affinity, selectivity, metabolic stability, and central nervous system penetration. Optimized analogs demonstrated improved metabolic stability and favorable brain exposure, supporting their potential as CNS-active agents. Spirocyclic azabicyclic scaffolds were investigated to modulate D4R affinity and selectivity. SAR analyses revealed that incorporation of spirocyclic frameworks maintains D4R affinity while maintaining acceptable pharmacokinetic properties. Finally, optimization of claudin-1 inhibitors identified structural features critical for potency and metabolic stability, advancing the development of small-molecule inhibitors targeting tight junction dysregulation in CRC. Collectively, this work establishes strategic medicinal chemistry approaches for tuning receptor affinity, selectivity, and pharmacokinetic properties to support the development of small-molecule therapeutics for neurodegenerative diseases and oncology.
Rights
The author holds the copyright to this work and any reuse or permissions must be obtained from the author directly.
Recommended Citation
Webster, Thomas, "Development of Small-Molecule Therapeutics Targeting Neurodegenerative Diseases and Oncology" (2026). Theses & Dissertations. 1044.
https://digitalcommons.unmc.edu/etd/1044