Studies in GPCR and Chromosomal Control

This dissertation is divided into two distinct parts. The first chapter is focused on regulation of serotonin receptors and signaling to address drug addiction, while the second chapter is focused on a novel synthetic approach towards a small molecule inhibitor of Ewing’s sarcoma. Drug addiction is a complex neurological illness that continue to plague society. While many neural networks are involved in the process, it is understood that serotonin receptors play a central role. Previous research has identified two serotonin receptors, 5-HT2AR and 5-HT2CR, to have a synergistic effect on cocaine-related impulsivity. Not only do they function as individual receptors in the process, but they also form functional hetero-dimers in which 5-HT2AR signaling is blunted. The goal of this research is to further probe the 2A:2C receptor system to better understand how they are involved in the relapse stage of drug addiction, as well as gain insight into the mechanisms and behavior of heterodimerization. This work was accomplished through novel syntheses of small molecule serotonin agonists and positive allosteric modulators targeting the two receptors, as well as peptide mimics of the transmembrane domains to control the receptor associations. Ewing’s Sarcoma is a malignant pediatric cancer found in bones and soft tissues. It is the second most diagnosed bone cancer found in children. Current treatment for this disease is limited as the origin and mechanisms of metastasis are poorly understood. Our collaborators at the Baylor College of Medicine performed high-throughput screening to identify potential small molecule regulators of this disease, in which they identified a lead compound which has a significant, selective effect on cell death for Ewing’s Sarcoma cancer cells. Original work on this molecule was hindered due to experimental challenges in this synthesis. The goal of this research was to develop a highly efficient and enantioselective synthesis to expediate future research.