具有高体内疗效的多功能D2/D3激动剂D-520：α-突触核蛋白聚集体毒性调节剂
Multifunctional D2/D3 agonist D-520 with high in vivo efficacy: modulator of toxicity of alpha-synuclein aggregates.
作者信息
Modi Gyan, Voshavar Chandrashekhar, Gogoi Sanjib, Shah Mrudang, Antonio Tamara, Reith Maarten E A, Dutta Aloke K
机构信息
Department of Pharmaceutical Sciences, Wayne State University , Detroit, Michigan 48202, United States.
出版信息
ACS Chem Neurosci. 2014 Aug 20;5(8):700-17. doi: 10.1021/cn500084x. Epub 2014 Jul 9.
Abstract
We have developed a series of dihydroxy compounds and related analogues based on our hybrid D2/D3 agonist molecular template to develop multifunctional drugs for symptomatic and neuroprotective treatment for Parkinson's disease (PD). The lead compound (-)-24b (D-520) exhibited high agonist potency at D2/D3 receptors and produced efficacious activity in the animal models for PD. The data from thioflavin T (ThT) assay and from transmission electron microscopy (TEM) analysis demonstrate that D-520 is able to modulate aggregation of alpha-synuclein (αSN). Additionally, coincubation of D-520 with αSN is able to reduce toxicity of preformed aggregates of αSN compared to control αSN alone. Finally, in a neuroprotection study with dopaminergic MN9D cells, D-520 clearly demonstrated the effect of neuroprotection from toxicity of 6-hydroxydopamine. Thus, compound D-520 possesses properties characteristic of multifunctionality conducive to symptomatic and neuroprotective treatment of PD.
摘要
基于我们的D2/D3混合型激动剂分子模板，我们开发了一系列二羟基化合物及相关类似物，以研制用于帕金森病（PD）症状性和神经保护治疗的多功能药物。先导化合物（-）-24b（D-520）在D2/D3受体上表现出高激动剂效力，并在PD动物模型中产生了有效的活性。硫黄素T（ThT）检测和透射电子显微镜（TEM）分析的数据表明，D-520能够调节α-突触核蛋白（αSN）的聚集。此外，与单独的对照αSN相比，D-520与αSN共同孵育能够降低αSN预形成聚集体的毒性。最后，在一项针对多巴胺能MN9D细胞的神经保护研究中，D-520清楚地证明了其对6-羟基多巴胺毒性的神经保护作用。因此，化合物D-520具有有利于PD症状性和神经保护治疗的多功能特性。
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