A<sub>2A</sub> Adenosine Receptor Antagonists and Their Efficacy in Rat Models of Parkinson’s Disease
Parkinson’s disease (PD) represents a growing challenge to global health, as it involves millions of people. The high grade of disability is due to the loss of dopaminergic neuron activity, and levodopa is the gold-standard therapy used to restore dopamine in the dopamine-denervated regions. Another...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-02-01
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| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/14/5/338 |
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| Summary: | Parkinson’s disease (PD) represents a growing challenge to global health, as it involves millions of people. The high grade of disability is due to the loss of dopaminergic neuron activity, and levodopa is the gold-standard therapy used to restore dopamine in the dopamine-denervated regions. Another therapeutic approach is the use of A<sub>2A</sub> adenosine receptor antagonists and, among them, istradefylline is the only one currently approved for therapy in association with levodopa. In this work, we synthesized A<sub>2A</sub> adenosine receptor antagonists represented by 9-ethyl-2,8-disubstituted adenine derivatives, which were tested at human adenosine receptors in binding and functional assays. These compounds showed A<sub>2A</sub> adenosine receptor-binding affinities in the low nanomolar range and <b>1</b>, <b>4</b>, and <b>5</b> exhibited good potency in the functional assays. Hence, they were evaluated in <i>in vivo</i> rat models of PD, where they were demonstrated to revert haloperidol-induced catalepsy and potentiate levodopa-induced contralateral rotations in 6-hydroxydopamine-lesioned rats. The most potent derivative, <b>4</b>, was then evaluated in the tacrine model, where it reduced the tremulous jaw movements, therefore demonstrating an action on parkinsonian tremor. These data revealed 8-ethoxy-2-phenethoxy-9-ethyladenine (<b>4</b>) as an A<sub>2A</sub> adenosine receptor antagonist endowed with antiparkinsonian effects and as a good candidate to treat the disease. |
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| ISSN: | 2073-4409 |