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Molecules 2017, 22(6), 1010; doi:10.3390/molecules22061010

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

School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
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Received: 15 May 2017 / Revised: 13 June 2017 / Accepted: 14 June 2017 / Published: 17 June 2017
(This article belongs to the Special Issue Polypharmacology and Multitarget Drug Discovery)
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Abstract

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. View Full-Text
Keywords: adenosine A2AR antagonist; monoamine oxidase B inhibitor; phenylxanthine derivatives; parkinson′s disease adenosine A2AR antagonist; monoamine oxidase B inhibitor; phenylxanthine derivatives; parkinson′s disease
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Wang, X.; Han, C.; Xu, Y.; Wu, K.; Chen, S.; Hu, M.; Wang, L.; Ye, Y.; Ye, F. Synthesis and Evaluation of Phenylxanthine Derivatives as Potential Dual A2AR Antagonists/MAO-B Inhibitors for Parkinson’s Disease. Molecules 2017, 22, 1010.

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