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DESIGN AND SYNTHESIS OF N-(3-HYDROXYPHENYL)-3,8-DIAZABICYCLO[3.2.1]OCTANES AS OPIOID RECEPTOR PROBES
Author ORCID Identifier
https://orcid.org/0009-0001-3492-8240
Date Available
4-21-2028
Year of Publication
2026
Document Type
Doctoral Dissertation
Degree Name
Doctor of Philosophy (PhD)
College
Pharmacy
Department/School/Program
Pharmaceutical Sciences
Faculty
Thomas E. Prisinzano
Faculty
David Feola
Abstract
N-(3-hydroxyphenyl)-3,8-diazabicyclo[3.2.1]octanes constitute a novel class of synthetic opioids with potent μ-opioid receptor (MOR) activity, discovered during efforts to identify more effective synthetic opioid rescue agents. Notably, atoxifent, a member of this class, exhibited potency exceeding morphine and comparable to fentanyl. This unexpected agonist activity highlights the scaffold’s unique structural features and offers an opportunity to investigate how specific modifications influence MOR activity.
To explore this, we assessed the impact of structural modifications to the phenolic hydroxyl group, the 3,8-diazabicyclo[3.2.1]octane core, and the 3-phenylpropyl chain of N-(3-hydroxyphenyl)-3,8-diazabicyclo[3.2.1]octane on MOR activity. The resulting analogues were evaluated in vitro for G-protein activation at the MOR, functional selectivity, opioid receptor specificity, and metabolic stability, and were further assessed in vivo for antinociceptive activity.
Collectively, the design, synthesis, and evaluation of these analogues demonstrate that structural modifications of N-(3-hydroxyphenyl)-3,8-diazabicyclo[3.2.1]octanes are generally tolerated and yield analogues with enhanced MOR activity. These findings provide an avenue for identifying optimized chemical probes to advance our understanding of opioid pharmacology.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2026.88
Archival?
Archival
Funding Information
This work was supported by the National Institutes of Health, including the National Institute on Drug Abuse (grant U01 DA051377) and the National Center for Advancing Translational Sciences (grant UL1TR001998).
Recommended Citation
Trivedi, Riya R., "DESIGN AND SYNTHESIS OF N-(3-HYDROXYPHENYL)-3,8-DIAZABICYCLO[3.2.1]OCTANES AS OPIOID RECEPTOR PROBES" (2026). Theses and Dissertations--Pharmacy. 175.
https://uknowledge.uky.edu/pharmacy_etds/175
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Medicinal and Pharmaceutical Chemistry Commons, Medicinal-Pharmaceutical Chemistry Commons, Pharmaceutics and Drug Design Commons
