DOI
https://doi.org/10.25772/X5Z6-SA06
Author ORCID Identifier
Defense Date
2020
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Pharmacology & Toxicology
First Advisor
Patrick M. Beardsley, PhD
Abstract
Fentanyl-related substances constitute a class of compounds that were originally developed in the latter half of the 20th century as combination analgesic-anesthetic agents. Today, many of these compounds have emerged in the recreational drug marketplace as adulterants to heroin, counterfeit prescription pills, and even as standalone products designed to circumvent drug control laws. The objective of this dissertation was to identify the structural determinants of fentanyl analogs that could affect the potency and efficacy for eliciting their therapeutic and toxic effects to identify candidates of potential therapeutic interest. To accomplish this objective, thirty-eight fentanyl-related substances, in addition to the MOR agonist standards fentanyl, morphine, and buprenorphine, were evaluated for their effects in adult male Swiss Webster mice on locomotion, as measured by distance traveled in the open field, nociception, as measured by tail-withdrawal latency in the warm-water tail-withdrawal test, and ventilation, as measured by respiratory rate, tidal volume, and minute volume. The substances included, but were not limited to, N-phenethyl-fluorinated fentanyl analogs, N-phenyl-fluorinated fentanyl analogs, N-phenyl-fluorinated butyrylfentanyl analogs, and N-phenyl-fluorinated valerylfentanyl analogs. The results of the present studies showed that subtle structural changes can have a profound influence on potencies for eliciting their effects between compounds, as well as differential potencies for their effects within compounds. In particular, isobutyrylfentanyl and para-methoxybutyrylfentanyl distinguished themselves for which, under the conditions tested, their protective indices (antinociception vs hypoventilation) were >10x that of both fentanyl and morphine. These findings have both confirmed previous reports and provided new insights into the structural determinants of the in vivo pharmacological effects of fentanyl-related substances that may further efforts to develop analgesics with fewer adverse effects. Overall, fentanyl-related substances, although problematic for their toxic effects, represent a diverse class of compounds that should be explored further for their potential clinical utility.
Rights
© 2020 Neil B. Varshneya
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-12-2020