# Development of a Potential Treatment for Polysubstance Use Disorders

> **NIH NIH F31** · VIRGINIA COMMONWEALTH UNIVERSITY · 2021 · $39,631

## Abstract

Project Summary
The long-term objective of this proposed research is to develop a potent and selective kappa opioid receptor
(KOR) agonist/mu opioid receptor (MOR) low-efficacy partial agonist as a potential treatment for polysubstance
use disorders. Not only are the opioid epidemic and the misuse/abuse of stimulants both major health
concerns on their own, but the two classes of drugs are often used concomitantly, resulting in polysubstance
use disorders. More specifically, the use of opioids and stimulants in combination has been shown to increase
neurotoxicity. The growing population of people suffering from these use disorders is under-served as there
are currently no FDA-approved therapeutics for either stimulant use disorders or polysubstance use disorders.
This makes the development of new treatment options imperative. Nalfurafine (NLF), a KOR agonist and MOR
partial agonist clinically approved to treat uremic pruritis in Japan, has yielded intriguing pharmacological
results; it is responsible for a decrease in both opioid and stimulant self-administration, doesn’t result in
tolerance or self-administration when used in isolation, yields conditioned place aversion only at high doses,
and importantly does not exhibit dysphoric effects. Despite these promising characteristics, NLF is not suitable
for repurposing due to its low distribution in the central nervous system, though it may act as a lead for further
exploration and development. Therefore, it is hypothesized that KOR agonist/MOR low-efficacy partial agonist
dual ligands will serve as effective medications to treat comorbid opioid and stimulant use disorders; further, it
is proposed that studying analogs of NLF will lead to the development of this treatment. In this scenario, a KOR
agonist will function to attenuate the rewarding effects of opioids and stimulants discouraging abuse, while a
MOR partial agonist will function to prevent any psychotomimetic effects typical of KOR agonists. This
hypothesis will be tested in three specific aims. In Aim 1, analogs of NLF will be designed and synthesized.
Aim 2 will then facilitate the in vitro testing of designed ligands and controls for binding affinity, selectivity,
potency, efficacy, and functional activity. The most promising ligands identified from Aim 2 will be subjected to
further testing for the determination of their pharmacodynamic profiles in Aim 3; this will include tests of in vivo
functional activity, efficacy, potency, time-course and receptor mediation using warm-water tail immersion
assays, as well as determination of behavioral effects via self-administration assays. Success of this program
will further understanding of NLF structure-activity relationships and lead to the development of a novel ligand
with potential as a treatment for polysubstance use disorders.

## Key facts

- **NIH application ID:** 10314452
- **Project number:** 1F31DA054796-01
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Celsey Mackenna St. Onge
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $39,631
- **Award type:** 1
- **Project period:** 2021-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10314452

## Citation

> US National Institutes of Health, RePORTER application 10314452, Development of a Potential Treatment for Polysubstance Use Disorders (1F31DA054796-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10314452. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*