Author ORCID Identifier

https://orcid.org/0000-0002-0840-9391

Year of Publication

2022

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Pharmacy

Department/School/Program

Pharmaceutical Sciences

First Advisor

Dr. Thomas E. Prisinzano

Abstract

One of the most prominent opioid analgesics in the United States is the high potency agonist fentanyl. It is used in the treatment of acute and chronic pain and as an anesthetic adjuvant. When used inappropriately, however, ingestion of just a few milligrams of fentanyl or other synthetic opioid can cause opioid-induced respiratory depression (OIRD), often leading to death. Currently, the treatment of choice for OIRD is the opioid receptor antagonist naloxone. Recent reports, however, suggest that higher doses or repeated dosing of naloxone (due to recurrence of respiratory depression) may be required to fully reverse fentanyl-induced respiratory depression, rendering this treatment inadequate. To combat this synthetic opioid overdose crisis, this research aims at identifying a novel opioid reversal agent with enhanced efficacy towards fentanyl and other synthetic opioids.

Following their design and synthesis, a series of naltrexone analogues were characterized for their ability to antagonize the effects of fentanyl in vitro utilizing a modified forskolin-induced cAMP accumulation assay. Lead analogues, possessing potent MOR antagonist activity, were further evaluated in vivo to determine their PK properties. Compounds possessing favorable PK profiles (rapid brain penetration, extended half-life) were additionally tested for their ability to inhibit opioid-induced antinociception in the hot-plate assay. The combination of data collected from these in vitro and in vivo studies guided the design of additional naltrexone analogues through an iterative SAR process. Utilizing this research strategy, several optimized opioid antagonists were successfully identified, providing promising leads in our search for an improved fentanyl overdose rescue agent.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2022.195

Funding Information

This study was supported by the National Institutes of Health grants (R01DA01851 and U01DA051377) from 2019 - 2022.

Available for download on Tuesday, May 21, 2024

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