# The development of delta opioid receptor agonists for the treatment of opioid withdrawal associated behaviors

> **NIH NIH UG3** · WASHINGTON UNIVERSITY · 2022 · $2,316,866

## Abstract

Project Summary
Chronic opioid use can lead to opioid induced hyperalgesia (OIH), which is a paradoxical increase in pain
sensitivity. Currently, the only specific treatment for OIH is opioid cessation. However, during this abstinence
period, patients suffer from their untreated pain as well as opioid withdrawal; and the majority of patients relapse
within the first year. As a result, OIH patients are particularly vulnerable to the development of opioid use
disorder. Novel targeted therapies that could alleviate OIH would result in decreased prescription opioid misuse
and abuse. The Pradhan lab has recently shown that δ opioid receptor (δOR) agonists can reduce OIH in a mouse
model. However, the development of δOR agonists has been limited by seizurogenic activity and tolerance. These
adverse effects appear to be ligand biased, and δOR agonists which favor G protein signaling over β-arrestin
recruitment have a reduced propensity to induce analgesic tolerance and pro-convulsant effects. PharmNovo has
developed novel G protein biased δOR agonists. Their lead compound, PN6047, is pre-clinically safe and effective
in animal models of chronic pain; does not produce convulsions and, shows little analgesic tolerance. The
objective of this proposal is to form an academic-industry collaboration to evaluate novel biased δOR agonists
for the treatment of OIH. In the UG3 phase, the Pradhan lab will test PN6047 and another lead compound,
PN6041 which has higher G-protein bias, in their models of OIH. Dr. Jutkiewicz will test these lead agonists for
adverse effects in models of seizurogenic activity and abuse liability. In parallel, PharmNovo will use the two lead
compounds to design and synthesize a limited catalogue of novel ligands with the aim to obtain the optimal
properties of high selectivity and potency, G protein bias, and good CNS penetrance. These compounds will be
screened in vitro by the Kelly Lab. The critical Go/No-Go milestone necessary to progress to the UH3 phase will
be the identification of at least one lead compound that is effective in models of OIH, is non-seizurogenic, lacks
abuse liability, and has a promising ADME/ toxicity profile; and if we produce at least 10 follow up agonists with
high selectivity and differential bias/efficacy. In the UH3 phase, approximately 12-15 compounds identified in
the UG3 phase will be fully characterized in cellular and brain membrane assays, with 6-10 of these tested for
efficacy in OIH models, for analgesic tolerance, potential development of opioid-induced hyperalgesia,
seizurogenic activity, and abuse potential. The most promising compounds will undergo commercial in silico and
in vitro ADME/PK and pre-regulatory toxicology testing. Finally, we expect that an emergent lead compound
will be suitable for in vivo acute toxicology, dose range finding/maximum tolerated dose testing and, if possible
within timescale and budget, repeated dose toxicity studies. If fully successful, the project will have gen...

## Key facts

- **NIH application ID:** 10730457
- **Project number:** 7UG3DA053094-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Amynah Amir Ali Pradhan
- **Activity code:** UG3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,316,866
- **Award type:** 7
- **Project period:** 2022-11-01 → 2025-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10730457

## Citation

> US National Institutes of Health, RePORTER application 10730457, The development of delta opioid receptor agonists for the treatment of opioid withdrawal associated behaviors (7UG3DA053094-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10730457. Licensed CC0.

---

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