Compound shows promise for minimizing erratic movements in Parkinson's patients

Date:
December 1, 2021
Source:
Texas Biomedical Research Institute
Summary:
A new study has identified a promising drug candidate to minimize
uncontrolled, erratic muscle movements, called dyskinesia,
associated with Parkinson's disease.



FULL STORY ==========================================================================
A new study from Texas Biomedical Research Institute (Texas Biomed)
and collaborators has identified a promising drug candidate to minimize uncontrolled, erratic muscle movements, called dyskinesia, associated
with Parkinson's disease.


==========================================================================
The small molecule, called PD13R, reduced dyskinesia by more than 85% in
the marmoset animal model of Parkinson's disease. And, the animals got
much better sleep taking this compound compared to another drug often prescribed for dyskinesia. The results were published in the journal Experimental Neurology.

Dyskinesia is a common side effect in patients with Parkinson's
disease. It is not a symptom of the disease itself, but typically emerges
about five years into taking levodopa, the leading medication used to
restore balance, reduce shaking and manage other motor control issues
patients experience.

"Levodopa is amazing, it works like magic, but it has side effects. If we
can eliminate these side effects, it could change the life of patients
with Parkinson's," says Marcel Daadi, PhD, an associate professor at
Texas Biomed and lead paper author.

Designing drugs for Parkinson's and its side effects is notoriously
difficult.

This is in part due to the progressive nature of the disease as neurons deteriorate, and because it involves the neurotransmitter dopamine. There
are five types of dopamine receptors, all with different functions,
yet very similar structures. Finding a compound that only interacts with
the desired receptor is a major challenge.

To try to identify a compound that only binds to dopamine receptor #3
(D3), Daadi teamed up with Southwest Research Institute. SwRI's drug
discovery software RhodiumTMidentified PD13R as a likely candidate and predicted how it would bind to D3. Daadi reached out to medicinal chemists
at Temple University to synthesize the compound, who are currently
working on this class of compounds for their antipsychotic properties.

Daadi and his team at Texas Biomed explored how well the compound
targeted the D3 receptor compared to the other dopamine receptors in
cell culture tests.

They found it had a 1,486-times higher selectivity for D3 than for D2,
which is the most similar in structure.

The team then administered PD13R to the marmoset animal model of
Parkinson's.

Like human patients, the nonhuman primates developed dyskinesia
after receiving levodopa. When treated with PD13R, dyskinesia dropped dramatically.

"We were very excited to see the robust antidyskinetic effect of the
drug," Daadi explains.

The animals wore activity monitors, and with PD13R, their activity was low
at night, when they normally sleep. In contrast, when given a different
drug currently on the market for dyskinesia, their nighttime activity
was significantly high, suggesting that PD13R may be a good treatment
option without this side effect.

Daadi and his team plan to continue with safety and efficacy studies
required by the U.S. Food and Drug Administration (FDA) before human
clinical trials can begin. "I am very hopeful we can move this into
Phase 1 clinical trials within two years," Daadi says.

This investigation used resources that were supported by the Southwest
National Primate Research Center grant P51 OD011133 from the Office of
Research Infrastructure Programs, National Institutes of Health. This
work was supported by the Worth Family Fund, The Perry and Ruby Stevens Charitable Foundation, The Robert J. Jr. and Helen C. Kleberg Foundation,
The Marmion Family Fund, The William and Ella Owens Medical Research Foundation, the National Institute on Aging R56 AG059284.

========================================================================== Story Source: Materials provided by
Texas_Biomedical_Research_Institute. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Thomas Oh, Elyas S. Daadi, Jeffrey Kim, Etienne W. Daadi,
Peng-Jen Chen,
Gourav Roy-Choudhury, Jonathan Bohmann, Benjamin E. Blass, Marcel M.

Daadi. Dopamine D3 receptor ligand suppresses the expression
of levodopa- induced dyskinesia in nonhuman primate model of
parkinson's disease.

Experimental Neurology, 2022; 347: 113920 DOI: 10.1016/
j.expneurol.2021.113920 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/12/211201150115.htm

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