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Novel inhibitors of human DOPA decarboxylase extracted from Euonymus glabra Roxb.

Abstract：

: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's 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 ± 1.6 and 21.6 ± 2.7 μM 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-activity 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.

journal_name

ACS Chem Biol

journal_title

ACS chemical biology

authors

Ren J,Zhang Y,Jin H,Yu J,Zhou Y,Wu F,Zhang W

doi

10.1021/cb500009r

subject

Has Abstract

pub_date

2014-04-18 00:00:00

pages

897-903

issue

4

eissn

1554-8929

issn

1554-8937

journal_volume

9

pub_type

杂志文章

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