Electronic Theses and Dissertations

Date of Award


Document Type


Degree Name

Ph.D. in Chemistry


Chemistry and Biochemistry

First Advisor

John M Rimolid

Second Advisor

David C. Stevens

Third Advisor

David A. Colby


Pain, although subjective, is an unpleasant sensation caused by a noxious stimulus, that effects millions of people every year. Currently, the most frequently prescribed class of analgesics for moderate to severe acute and sometime chronic pain are opioid analgesics, most commonly ?-opioid receptor (MOP) agonists, such as oxycodone, morphine, and fentanyl. Although these drugs provide significant pain relief, they are also associated with unwelcome side effects such as constipation, addiction, physical dependence, respiratory depression, and physiological tolerance that leads to hyperalgesia. Receptor desensitization due to excessive receptor activation by an agonist is but one source of physiological tolerance; it can also develop through the activation of homeostasis-regulating endogenous anti-opioid systems. One of these anti-opioid systems, the neuropeptide FF (NPFF) system, which is comprised of two receptor subtypes NPFF1 and NPFF2, is a member of the RFamide family and has been shown to modulate opioid activity. Although, currently, there are limited numbers of reported NPFFR ligands, it has been indicated that antagonism of NPFFR leads to the attenuation of physiological tolerance. Currently, many of these ligands are peptidic in structure and are not considered ideal candidates for drug development. However, the design and synthesis of small molecule, dual-acting ligands that act as MOP agonists and NPFF antagonists are a viable approach to opioid analgesics. These ligands would provide the necessary opportunity to provide analgesia, while also blocking a physiological tolerance development center, thus preventing the development of hyperalgesia as well as provide an opioid drug class with reduced side effect liabilities.

Available for download on Thursday, July 23, 2020

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