# Exploiting Dopamine Receptor Functional Selectivity as an Approach to Treat Parkinson's Symptoms

> **NIH NIH R01** · DUKE UNIVERSITY · 2020 · $638,745

## Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by severe motor deficits caused by the
progressive loss of striatal dopamine (DA) input and it is commonly treated with the DA precursor L-DOPA or by DA
D2 receptor (D2R) agonists. Although L-DOPA ameliorates the motor deficits, prolonged use leads to motor
abnormalities, termed L-DOPA-induced dyskinesias. Despite these limitations, L-DOPA is the mainstay for PD
treatment. Various animal models of PD suggest that dyskinesias are associated with enhanced G-protein mediated
signaling at DA receptors (DARs) and this leads to changes in gene expression and uncontrolled neuronal excitability.
Research over the past decade has shown that DARs can signal not only through G-proteins, but also also through β-
arrestin2 (βarr2) scaffolds containing signaling complexes that initiate intracellular signals distinct from those of G-
proteins. Recently we have demonstrated in PD models that over-expression of βarr2 in the striata of mouse, rat, or
macaque reduces L-DOPA-induced dyskinesias. This novel approach facilitated locomotion and simultaneously
desensitized G-protein signaling, thereby reducing the dyskinesia without potentially affecting other neurotransmitter
systems. The Overall Goal of the proposed research is to provide preclinical results for taking novel D1R and
D2R βarr-biased compounds into clinical PD trials. Our Central Hypothesis is that small molecule drugs that
selectively activate the βarr, but not the G-protein, pathway at D1Rs/D2Rs will have anti-parkinsonian activities without
inducing dyskinesias. We have three Specific Aims. Aim 1 will develop βarr-biased D1R and D2R ligands from the
leads/hits we recently discovered. Aim 2 will assess the in vitro profile of the newly synthesized βarr-biased
compounds. Aim 3 will determine the in vivo effects of D1R and D2R βarr-biased compounds in animal
models of PD.

## Key facts

- **NIH application ID:** 9868334
- **Project number:** 5R01NS100930-04
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Marc G. Caron
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $638,745
- **Award type:** 5
- **Project period:** 2017-05-15 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9868334

## Citation

> US National Institutes of Health, RePORTER application 9868334, Exploiting Dopamine Receptor Functional Selectivity as an Approach to Treat Parkinson's Symptoms (5R01NS100930-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9868334. Licensed CC0.

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