Author ORCID Identifier

Defense Date


Document Type


Degree Name

Doctor of Philosophy


Pharmaceutical Sciences

First Advisor

Yan Zhang, PhD


The overdose crisis, intensified by polysubstance use, necessitates effective strategies including the development of non-addictive pain medications and substance use disorder treatments. This project aims to address gaps in current treatment options by developing a treatment for concurrent opioid and stimulant substance use disorders and a non-addictive pain medication, contributing to a comprehensive crisis response.

Nalfurafine was chosen as a lead due to its intriguing pharmacological profile and mild side effects. Thus, its structure-activity relationships were systematically studied through the design, synthesis, and evaluation of twenty-four analogs. Competitive radioligand and [35S]GTPγS binding assays were used to determine binding affinity, selectivity, efficacy, and functional activity for the KOR, MOR, and DOR.

Analogs were then further tested for their opioid agonism and identified hits progressed to studies of dose-response, time-course, and receptor selectivity using warm-water tail immersion assays in mice. A naloxone challenge assessed the dependence produced by chronic administration of the hits and a drug distribution study assessed their ability to penetrate the blood-brain barrier, both in mice. Moreover, self-administration assays were utilized to identify potential abuse liability in rats. The most promising compound addressing the substance use disorder treatment development hypothesis was characterized through self-administration assays to determine its effectiveness to reduce fentanyl/cocaine mixture self-administration in rats using a drug-food choice procedure. Additionally, two compounds were studied for potential pain management purposes. Assays assessing development of tolerance and weight fluctuations with chronic treatment as well as cross-tolerance with morphine and effects on locomotor activity were performed in mice.


© Celsey M. St. Onge

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission


Available for download on Tuesday, July 04, 2028