Novel inhibitors of human DOPA decarboxylase extracted from Euonymus glabra Roxb.
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.
Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, ‡School of Pharmacy, and §State Key Laboratory of Microbial Metabolism & School of Life Sciences and Biotechnology, Shanghai Jiao Tong University , Shanghai 200240, China.
Jie
J
Ren
Yuanyuan
Y
Zhang
Huizi
H
Jin
Jing
J
Yu
Yueyang
Y
Zhou
Fang
F
Wu
Weidong
W
Zhang
D065105:Aromatic Amino Acid Decarboxylase Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*; D002478:Cells, Cultured; D004296:Dopa Decarboxylase / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D029756:Euonymus / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D010300:Parkinson Disease / Q000188:drug therapy
D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D004296:Dopa Decarboxylase