Date of Award
5-12-2024
Degree Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Chemistry
Advisor(s)
Rachel Steinhardt
Keywords
Dopamine;GPCR;Medicinal;Organic;Proteomics;Serotonin
Subject Categories
Chemistry | Physical Sciences and Mathematics
Abstract
Dopaminergic and serotonergic signaling pathways are involved in numerous biological processes including behavior, mood regulation, and cognition. Dysfunction in these pathways can lead to neurological and mental health disorders, which are often treated with drugs targeting the dopamine and serotonin receptors. However, many of these drugs, along with those targeting other G protein couple receptors (GPCRs), suffer a lack of target specificity, leading to nonspecific binding and therefore side effects. In recent years, new advances in chemical biological techniques, including affinity-based protein profiling (ABPP) and optogenetics, have further elucidated the structure and function of GPCRs, which can in turn aid in the design of improved drugs. In this work, we demonstrate the use of (1) Photoaffinity labels to investigate drug-active site interactions and off-target binding of dopamine receptor D2 agonists; and (2) A light-responsive agonist-antagonist ligand pair for spatiotemporal control and study of serotonin receptor 2C (5HT2C) signaling. Ongoing research involves functional and binding assays of a novel clozapine-based covalent antagonist of serotonin receptor 2A (5HT2A), which can be used as a drug or probe. Taken together, these efforts represent an advancement in the field of chemical biology for the study of membrane-bound neuroreceptors. The insights gained from this work can be used to inform the development of more effective, subtype-specific small molecule therapeutics for the treatment of diseases including schizophrenia, drug addiction, and Parkinson’s Disease.
Access
Open Access
Recommended Citation
Doukmak, Emma Joanna, "A Molecular Toolbox to Study Dopamine and Serotonin Receptors for the Development of Improved Therapeutics" (2024). Dissertations - ALL. 1970.
https://surface.syr.edu/etd/1970
