# Negative allosteric modulators of the D3 dopamine receptor as therapeutic leads for substance use disorders

> **NIH NIH UG3** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $194,375

## Abstract

Title: Negative allosteric modulators of the D3 dopamine receptor as therapeutic leads
for substance use disorders
Summary: Dopamine receptors (DRs) play a critical role in cell signaling processes and
modulation of information transfer within the nervous system. DRs comprise five distinct
subtypes subdivided into two families, D1-like (D1R and D5R) and D2-like (D2R, D3R,
and D4R), that produce profoundly diverse physiological effects. In particular, D3R
antagonists have been investigated as a therapeutic approach to treating substance use
disorders (SUDs), both in disrupting drug seeking motivation and preventing relapse.
Drug overdose deaths have more than doubled in the past decade driven largely by rising
opioid abuse, underscoring the urgent need to identify new SUD therapies that are
effective for opioid SUD. Recent evidence suggests that D3R antagonism may be an
especially effective treatment for opioid SUD. However, the high sequence homology
shared by the D3R and other GPCRs within their orthosteric binding sites has made the
discovery of highly selective compounds difficult, leading to the potential for off-target side
effects due to simultaneous receptor modulation by such agents. It is now appreciated
that, in addition to highly conserved orthosteric sites, many G protein-coupled receptors,
including DRs, possess distinct and non-conserved allosteric sites. Thus, compounds that
modulate receptors through the interaction with an allosteric site have the potential to be
profoundly selective. Here we seek to develop structurally novel D3R negative allosteric
modulators that possess exceptional D3R selectivity as new chemical probes and
therapeutic leads, in an overarching goal to support development of a D3R antagonist
SUD therapy. In an effort to discover highly selective allosteric antagonists for the D3R,
we employed a high-throughput screen of the NIH small molecule library. The library was
initially screened using a D3R-mediated β-arrestin recruitment assay. Antagonist hits
were counter-screened for radioligand displacement using an orthosteric ligand, which
led to the identification of three promising hit compounds with allosteric properties. In this
study, we will develop flexible, robust synthetic routes to each scaffold to facilitate
medicinal chemistry. Analogs of the three scaffolds will be evaluated for potency, D3R
selectivity and preliminary in vitro pharmacokinetic properties to identify the most
promising series to advance for iterative medicinal chemistry optimization. The most
promising series will be further optimized with an emphasis on the requisite properties for
an in vivo probe compound. The probe will be intensively characterized for D3R selectivity
in several functional outputs including β-arrestin recruitment and G-protein activation.
Schild-type functional assays will be used to confirm that this compound acts in a non-
competitive manner at the D3R. Finally, in vivo pharmacokinetic experiments will provide
a ...

## Key facts

- **NIH application ID:** 10411908
- **Project number:** 5UG3DA050820-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Kevin J. Frankowski
- **Activity code:** UG3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $194,375
- **Award type:** 5
- **Project period:** 2021-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10411908

## Citation

> US National Institutes of Health, RePORTER application 10411908, Negative allosteric modulators of the D3 dopamine receptor as therapeutic leads for substance use disorders (5UG3DA050820-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10411908. Licensed CC0.

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