Discovery of indolylpiperazinylpyrimidines with dual-target profiles at adenosine A2A and dopamine D2 receptors for Parkinson's disease treatment.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra of the human brain, leading to depletion of dopamine production. Dopamine replacement therapy remains the mainstay for attenuation of PD symptoms. Nonethele...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2018-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5755735?pdf=render |
| _version_ | 1818132502098739200 |
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| author | Yi-Ming Shao Xiaohua Ma Priyankar Paira Aaron Tan Deron Raymond Herr Kah Leong Lim Chee Hoe Ng Gopalakrishnan Venkatesan Karl-Norbert Klotz Stephanie Federico Giampiero Spalluto Siew Lee Cheong Yu Zong Chen Giorgia Pastorin |
| author_facet | Yi-Ming Shao Xiaohua Ma Priyankar Paira Aaron Tan Deron Raymond Herr Kah Leong Lim Chee Hoe Ng Gopalakrishnan Venkatesan Karl-Norbert Klotz Stephanie Federico Giampiero Spalluto Siew Lee Cheong Yu Zong Chen Giorgia Pastorin |
| author_sort | Yi-Ming Shao |
| collection | DOAJ |
| description | Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra of the human brain, leading to depletion of dopamine production. Dopamine replacement therapy remains the mainstay for attenuation of PD symptoms. Nonetheless, the potential benefit of current pharmacotherapies is mostly limited by adverse side effects, such as drug-induced dyskinesia, motor fluctuations and psychosis. Non-dopaminergic receptors, such as human A2A adenosine receptors, have emerged as important therapeutic targets in potentiating therapeutic effects and reducing the unwanted side effects. In this study, new chemical entities targeting both human A2A adenosine receptor and dopamine D2 receptor were designed and evaluated. Two computational methods, namely support vector machine (SVM) models and Tanimoto similarity-based clustering analysis, were integrated for the identification of compounds containing indole-piperazine-pyrimidine (IPP) scaffold. Subsequent synthesis and testing resulted in compounds 5 and 6, which acted as human A2A adenosine receptor binders in the radioligand competition assay (Ki = 8.7-11.2 μM) as well as human dopamine D2 receptor binders in the artificial cell membrane assay (EC50 = 22.5-40.2 μM). Moreover, compound 5 showed improvement in movement and mitigation of the loss of dopaminergic neurons in Drosophila models of PD. Furthermore, in vitro toxicity studies on compounds 5 and 6 did not reveal any mutagenicity (up to 100 μM), hepatotoxicity (up to 30 μM) or cardiotoxicity (up to 30 μM). |
| first_indexed | 2024-12-11T08:37:51Z |
| format | Article |
| id | doaj.art-950334628e1d476da403804a28267629 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-11T08:37:51Z |
| publishDate | 2018-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-950334628e1d476da403804a282676292022-12-22T01:14:19ZengPublic Library of Science (PLoS)PLoS ONE1932-62032018-01-01131e018821210.1371/journal.pone.0188212Discovery of indolylpiperazinylpyrimidines with dual-target profiles at adenosine A2A and dopamine D2 receptors for Parkinson's disease treatment.Yi-Ming ShaoXiaohua MaPriyankar PairaAaron TanDeron Raymond HerrKah Leong LimChee Hoe NgGopalakrishnan VenkatesanKarl-Norbert KlotzStephanie FedericoGiampiero SpallutoSiew Lee CheongYu Zong ChenGiorgia PastorinParkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra of the human brain, leading to depletion of dopamine production. Dopamine replacement therapy remains the mainstay for attenuation of PD symptoms. Nonetheless, the potential benefit of current pharmacotherapies is mostly limited by adverse side effects, such as drug-induced dyskinesia, motor fluctuations and psychosis. Non-dopaminergic receptors, such as human A2A adenosine receptors, have emerged as important therapeutic targets in potentiating therapeutic effects and reducing the unwanted side effects. In this study, new chemical entities targeting both human A2A adenosine receptor and dopamine D2 receptor were designed and evaluated. Two computational methods, namely support vector machine (SVM) models and Tanimoto similarity-based clustering analysis, were integrated for the identification of compounds containing indole-piperazine-pyrimidine (IPP) scaffold. Subsequent synthesis and testing resulted in compounds 5 and 6, which acted as human A2A adenosine receptor binders in the radioligand competition assay (Ki = 8.7-11.2 μM) as well as human dopamine D2 receptor binders in the artificial cell membrane assay (EC50 = 22.5-40.2 μM). Moreover, compound 5 showed improvement in movement and mitigation of the loss of dopaminergic neurons in Drosophila models of PD. Furthermore, in vitro toxicity studies on compounds 5 and 6 did not reveal any mutagenicity (up to 100 μM), hepatotoxicity (up to 30 μM) or cardiotoxicity (up to 30 μM).http://europepmc.org/articles/PMC5755735?pdf=render |
| spellingShingle | Yi-Ming Shao Xiaohua Ma Priyankar Paira Aaron Tan Deron Raymond Herr Kah Leong Lim Chee Hoe Ng Gopalakrishnan Venkatesan Karl-Norbert Klotz Stephanie Federico Giampiero Spalluto Siew Lee Cheong Yu Zong Chen Giorgia Pastorin Discovery of indolylpiperazinylpyrimidines with dual-target profiles at adenosine A2A and dopamine D2 receptors for Parkinson's disease treatment. PLoS ONE |
| title | Discovery of indolylpiperazinylpyrimidines with dual-target profiles at adenosine A2A and dopamine D2 receptors for Parkinson's disease treatment. |
| title_full | Discovery of indolylpiperazinylpyrimidines with dual-target profiles at adenosine A2A and dopamine D2 receptors for Parkinson's disease treatment. |
| title_fullStr | Discovery of indolylpiperazinylpyrimidines with dual-target profiles at adenosine A2A and dopamine D2 receptors for Parkinson's disease treatment. |
| title_full_unstemmed | Discovery of indolylpiperazinylpyrimidines with dual-target profiles at adenosine A2A and dopamine D2 receptors for Parkinson's disease treatment. |
| title_short | Discovery of indolylpiperazinylpyrimidines with dual-target profiles at adenosine A2A and dopamine D2 receptors for Parkinson's disease treatment. |
| title_sort | discovery of indolylpiperazinylpyrimidines with dual target profiles at adenosine a2a and dopamine d2 receptors for parkinson s disease treatment |
| url | http://europepmc.org/articles/PMC5755735?pdf=render |
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