Wang Xuebao, Han Chao, Xu Yong, Wu Kaiqi, Chen Shuangya, Hu Mangsha, Wang Luyao, Ye Yun, Ye Faqing
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
Molecules. 2017 Jun 17;22(6):1010. doi: 10.3390/molecules22061010.
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 and 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.
本研究的目的是证实苯黄嘌呤（PX）衍生物具有腺苷A2A受体（A2AR）阻断特性这一推测，并筛选和评估这些PX衍生物作为治疗帕金森病的双重A2AR拮抗剂/单胺氧化酶B（MAO-B）抑制剂。为探究这一假设，制备了两个系列的PX衍生物，并在体外测定了它们对A2AR的拮抗作用和对MAO-B的抑制作用。为进一步评估其抗帕金森病特性，在体内进行了药代动力学和氟哌啶醇诱导的僵住症实验。PX-D和PX-E类似物作为有效的A2AR拮抗剂，其抑制常数（Ki值）范围为0.27至10 μM，并且这些类似物表现出相对温和的MAO-B抑制效力，抑制剂解离常数（Ki值）范围为0.25至10 μM。此外，化合物 和 在氟哌啶醇诱导的僵住症实验中表现出有效的抗帕金森病特性，证实这两种化合物是有效的A2AR拮抗剂和MAO-B抑制剂。我们得出结论，PX-D和PX-E类似物是一类有前景的用于治疗帕金森病的双效化合物候选物。
