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https://hdl.handle.net/2440/124495
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Type: | Journal article |
Title: | Discovery of indolylpiperazinylpyrimidines with dual-target profiles at adenosine A₂A and dopamine D₂ receptors for Parkinson’s disease treatment |
Other Titles: | Discovery of indolylpiperazinylpyrimidines with dual-target profiles at adenosine A(2A) and dopamine D(2) receptors for Parkinson's disease treatment |
Author: | Shao, Y.M. Ma, X. Paira, P. Tan, A. Herr, D.R. Lim, K.L. Ng, C.H. Venkatesan, G. Klotz, K.N. Federico, S. Spalluto, G. Cheong, S.L. Chen, Y.Z. Pastorin, G. |
Citation: | PLoS One, 2018; 13(1):e0188212-e0188212 |
Publisher: | PLoS ONE |
Issue Date: | 2018 |
ISSN: | 1932-6203 1932-6203 |
Editor: | Blum, D. |
Statement of Responsibility: | Yi-Ming Shao, Xiaohua Ma, Priyankar Paira, Aaron Tan, Deron Raymond Herr, Kah Leong Lim ... et al. |
Abstract: | 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). |
Keywords: | CHO Cells Animals Animals, Genetically Modified Humans Cricetulus Drosophila Parkinsonian Disorders Parkinson Disease Piperazines Pyrimidines Receptors, Dopamine D2 Receptor, Adenosine A2A Dopamine Agonists Antiparkinson Agents Radioligand Assay Drug Evaluation, Preclinical Drug Discovery Adenosine A2 Receptor Antagonists Support Vector Machine Adenylyl Cyclase Inhibitors |
Rights: | © 2018 Shao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
DOI: | 10.1371/journal.pone.0188212 |
Published version: | http://dx.doi.org/10.1371/journal.pone.0188212 |
Appears in Collections: | Aurora harvest 4 Medicine publications |
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