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Author ORCID Identifier
Date Available
5-8-2027
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
Activation of the kappa opioid receptor (KOR) has been shown to produce analgesia but does not lead respiratory depression, tolerance, or constipation like mu opioid receptor (MOR). KOR agonists have been identified as potential therapeutic treatments for pain, substance use disorders and remyelinating pharmacotherapies. However, typical KOR agonists’ side effects include sedation, dysphoria, and anxiety have limited clinical development. This inspired us to search for a refined KOR agonist that retains the positive pharmacological effects with reduced side effects. A refined compound would serve as a study tool to further develop KOR agonist as therapeutic treatment.
To achieve our goal, our first strategy included leveraging a “privileged structure” KOR agonist, tifluadom, a 1,4-benzodiazapene with no activity at GABAA but full agonistic activity at KOR and MOR. A library of tifluadom analogues were designed, synthesized, and evaluated in vitro and in vivo. While we were able to identify dual KOR/MOR probes with reduced ꞵ-arrestin2 recruitment compared to tifluadom, these analogues had short duration of action. This was possibly due to the 1,4-benzodiazapene core being quickly metabolized which hindered our goal.
Our next strategy was to further study the arylacetamide scaffold which includes the typical KOR agonist, (±)-U50,488. The first three synthesized analogues showed full agonist activity at KOR with varying signaling bias profiles in our in vitro tests and were ~10 times more potent than (±)-U50,488 in an antinociception model. Significantly, our lead analog showed reduced sedation, anxiety, and aversion that are typically associated with KOR agonists. This was hypothesized due to the differences in the LogD value and the stereochemical structure.
In an effort to understand further about our lead analog chemically, several analogues were synthesized. To our surprise, moving the nitrogen in the pyridine ring from the 3- to the 2-position showed an increase of 10-fold in potency, comparable to nalfurafine and EOM-Sal B, which are the two most active KOR agonists. An active enantiomer form was identified and synthesized and are currently being investigated for their side effect profile.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2026.109
Archival?
Archival
Recommended Citation
Vu, Loan Y., "Design and Synthesis of a Refined Kappa Opioid Agonist with Reduced Sedation, Anxiety, and Aversion" (2026). Theses and Dissertations--Pharmacy. 176.
https://uknowledge.uky.edu/pharmacy_etds/176
