# Discovery and characterization of selective D4R antagonists and their evaluation in preclinical models of PD-LIDs

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2022 · $395,322

## Abstract

PROJECT SUMMARY:
Parkinson’s disease (PD) is a chronic and progressive neurodegenerative disorder characterized by the cardinal motor
symptoms of resting tremor, hypokinesia, muscle rigidity and bradykinesia. To date, dopamine replacement therapy using
the dopamine precursor levodopa, or L-DOPA, remains the gold standard treatment for the motor symptoms in PD.
However, development of L-DOPA-induced dyskinesias (LIDs) represents a major dose-limiting adverse effect associated
with the long-term treatment of PD using L-DOPA. For example, approximately 10% of PD patients per year develop
LIDs within the first 7-8 years of L-DOPA treatment. Moreover, there are no effective treatments for either preventing the
development of LIDs or reversing already established LIDs in PD patients. To date, there remains a critical unmet need
to develop novel therapeutic approaches for the complications associated with chronic L-DOPA treatment in PD. We
have recently discovered a series of dopamine 4 receptor antagonists which are potent and selective for the D4 receptor
over the other dopamine isoforms, and a wide selectivity panel. In addition, we have shown that a prototypical compound
from this scaffold was capable of producing antidyskinetic action in a mouse model. Subsequently, we have discovered
two additional novel scaffolds that show excellent potency and selectivity as D4 antagonists. In this proposal, we will
improve and optimize our lead scaffolds in order to improve the ADME properties (metabolic stability) while maintaining
the potency and selectivity. In order to develop these best-in-class compounds, we will utilize an iterative medicinal
chemistry approach and integrated DMPK studies which will allow us to evaluate potency and selectivity, but also the in
vitro and in vivo DMPK properties of newly made compound in a timely manner. The advanced D4 receptor antagonist
compounds will then be evaluated in an in vivo animal model of LIDs. These selective D4 receptor antagonist will offer a
unique opportunity to help advance the field toward a first-in-class therapeutic agent.

## Key facts

- **NIH application ID:** 10434146
- **Project number:** 5R01NS119266-02
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Corey R. Hopkins
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $395,322
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10434146

## Citation

> US National Institutes of Health, RePORTER application 10434146, Discovery and characterization of selective D4R antagonists and their evaluation in preclinical models of PD-LIDs (5R01NS119266-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10434146. Licensed CC0.

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