Novel Inhibitors of Human DOPA Decarboxylase Extracted from Euonymus glabra Roxb.

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• 作者：Jie Ren ; Yuanyuan Zhang ; Huizi Jin ; Jing Yu ; Yueyang Zhou ; Fang Wu ; Weidong Zhang
• 刊名：ACS Chemical Biology
• 出版年：2014
• 出版时间：April 18, 2014
• 年：2014
• 卷：9
• 期：4
• 页码：897-903
• 全文大小：346K
• 年卷期：v.9,no.4(April 18, 2014)
• ISSN：1554-8937

文摘

Dopamine, a biogenic amine with important biological functions, is produced from l-DOPA by DOPA decarboxylase (DDC). DDC is a potential target to modulate the production of dopamine in several pathological states. Known inhibitors of DDC have been used for treatment of Parkinson鈥檚 disease but suffered low specificity and diverse side effects. In the present study, we identified and characterized a novel class of natural-product-based selective inhibitors for DDC from the extract of Euonymus glabra Roxb. by a newly developed high-throughput enzyme assay. The structures of these inhibitors are dimeric diarylpropane, a unique chemical structure containing a divalent dopamine motif. The most effective inhibitors 5 and 6 have an IC₅₀ of 11.5 卤 1.6 and 21.6 卤 2.7 渭M in an in vitro purified enzyme assay, respectively, but did not inhibit other homologous enzymes. Compound 5 but not 6 dose-dependently suppressed the activity of hDDC and dopamine levels at low micromolar concentrations in cells. Furthermore, structure鈥揳ctivity relationship analyses revealed that p-benzoquinone might be a crucial moiety of these inhibitors for inhibiting hDDC. The natural-product-based selective inhibitors of hDDC could serve as a chemical lead for developing improved drugs for dopamine-related disease states.