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Synthesis and Evaluation of Phenylxanthine Derivatives as Potential Dual A2AR Antagonists/MAO-B Inhibitors for Parkinson’s Disease

The aim of this research was to prove the speculation that phenylxanthine (PX) derivatives possess adenosine A2A receptor (A2AR)-blocking properties and to screening and evaluate these PX derivatives as dual A2AR antagonists/MAO-B inhibitors for Parkinson′s disease. To explore this hypothesis, two s...

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Autores principales: Wang, Xuebao, Han, Chao, Xu, Yong, Wu, Kaiqi, Chen, Shuangya, Hu, Mangsha, Wang, Luyao, Ye, Yun, Ye, Faqing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6152622/
https://www.ncbi.nlm.nih.gov/pubmed/28629145
http://dx.doi.org/10.3390/molecules22061010
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author Wang, Xuebao
Han, Chao
Xu, Yong
Wu, Kaiqi
Chen, Shuangya
Hu, Mangsha
Wang, Luyao
Ye, Yun
Ye, Faqing
author_facet Wang, Xuebao
Han, Chao
Xu, Yong
Wu, Kaiqi
Chen, Shuangya
Hu, Mangsha
Wang, Luyao
Ye, Yun
Ye, Faqing
author_sort Wang, Xuebao
collection PubMed
description The aim of this research was to prove the speculation that phenylxanthine (PX) derivatives possess adenosine A2A receptor (A2AR)-blocking properties and to screening and evaluate these PX derivatives as dual A2AR antagonists/MAO-B inhibitors for Parkinson′s disease. To explore this hypothesis, two series of PX derivatives were prepared and their antagonism against A2AR and inhibition against MAO-B were determined in vitro. In order to evaluate further the antiparkinsonian properties, pharmacokinetic and haloperidol-induced catalepsy experiments were carried out in vivo. The PX-D and PX-E analogues acted as potent A2AR antagonists with Ki values ranging from 0.27 to 10 μM, and these analogues displayed relatively mild MAO-B inhibition potencies, with inhibitor dissociation constants (Ki values) ranging from 0.25 to 10 μM. Further, the compounds PX-D-P6 and PX-E-P8 displayed efficacious antiparkinsonian properties in haloperidol-induced catalepsy experiments, verifying that these two compounds were potent A2AR antagonists and MAO-B inhibitors. We conclude that PX-D and PX-E analogues are a promising candidate class of dual-acting compounds for treating Parkinson′s disease.
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spelling pubmed-61526222018-11-13 Synthesis and Evaluation of Phenylxanthine Derivatives as Potential Dual A2AR Antagonists/MAO-B Inhibitors for Parkinson’s Disease Wang, Xuebao Han, Chao Xu, Yong Wu, Kaiqi Chen, Shuangya Hu, Mangsha Wang, Luyao Ye, Yun Ye, Faqing Molecules Article The aim of this research was to prove the speculation that phenylxanthine (PX) derivatives possess adenosine A2A receptor (A2AR)-blocking properties and to screening and evaluate these PX derivatives as dual A2AR antagonists/MAO-B inhibitors for Parkinson′s disease. To explore this hypothesis, two series of PX derivatives were prepared and their antagonism against A2AR and inhibition against MAO-B were determined in vitro. In order to evaluate further the antiparkinsonian properties, pharmacokinetic and haloperidol-induced catalepsy experiments were carried out in vivo. The PX-D and PX-E analogues acted as potent A2AR antagonists with Ki values ranging from 0.27 to 10 μM, and these analogues displayed relatively mild MAO-B inhibition potencies, with inhibitor dissociation constants (Ki values) ranging from 0.25 to 10 μM. Further, the compounds PX-D-P6 and PX-E-P8 displayed efficacious antiparkinsonian properties in haloperidol-induced catalepsy experiments, verifying that these two compounds were potent A2AR antagonists and MAO-B inhibitors. We conclude that PX-D and PX-E analogues are a promising candidate class of dual-acting compounds for treating Parkinson′s disease. MDPI 2017-06-17 /pmc/articles/PMC6152622/ /pubmed/28629145 http://dx.doi.org/10.3390/molecules22061010 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wang, Xuebao
Han, Chao
Xu, Yong
Wu, Kaiqi
Chen, Shuangya
Hu, Mangsha
Wang, Luyao
Ye, Yun
Ye, Faqing
Synthesis and Evaluation of Phenylxanthine Derivatives as Potential Dual A2AR Antagonists/MAO-B Inhibitors for Parkinson’s Disease
title Synthesis and Evaluation of Phenylxanthine Derivatives as Potential Dual A2AR Antagonists/MAO-B Inhibitors for Parkinson’s Disease
title_full Synthesis and Evaluation of Phenylxanthine Derivatives as Potential Dual A2AR Antagonists/MAO-B Inhibitors for Parkinson’s Disease
title_fullStr Synthesis and Evaluation of Phenylxanthine Derivatives as Potential Dual A2AR Antagonists/MAO-B Inhibitors for Parkinson’s Disease
title_full_unstemmed Synthesis and Evaluation of Phenylxanthine Derivatives as Potential Dual A2AR Antagonists/MAO-B Inhibitors for Parkinson’s Disease
title_short Synthesis and Evaluation of Phenylxanthine Derivatives as Potential Dual A2AR Antagonists/MAO-B Inhibitors for Parkinson’s Disease
title_sort synthesis and evaluation of phenylxanthine derivatives as potential dual a2ar antagonists/mao-b inhibitors for parkinson’s disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6152622/
https://www.ncbi.nlm.nih.gov/pubmed/28629145
http://dx.doi.org/10.3390/molecules22061010
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