Institute of Pharmaceutical Analysis, Faculty of Pharmacy, University of Szeged, Szeged, Hungary; Acheuron Hungary Ltd., Szeged, Hungary.
Department of Pharmacognosy, University of Szeged, Szeged, Hungary.
Phytomedicine. 2017 Oct 15;34:44-49. doi: 10.1016/j.phymed.2017.06.006. Epub 2017 Jul 3.
Transient Receptor Potential Vanilloid 1 (TRPV1) confers noxious heat and inflammatory pain signals in the peripheral nervous system. Clinical trial of resiniferatoxin from Euphorbia species is successfully aimed at TRPV1 in cancer pain management and heading toward new selective painkiller status that further validates this target for drug discovery efforts. Evodia species, used in traditional medicine for hundreds of years, are a recognised source of different TRPV1 agonists, but no antagonist has yet been reported.
HYPOTHESIS/PURPOSE: In a search for painkiller leads, we noted for the first time a TRPV1 antagonist activity in the fresh fruits of Tetradium daniellii (Benn.) T.G. Hartley (syn. Evodia hupehensis Dode).
Through a combination of extraction and purification methods with functional TRPV1-specific Ca uptake assays (bioactivity-guided fractionation/isolation/purification); we isolated a new painkiller candidate that is a distant structural homologue of capsiate exovanilloids and endovanilloids such as anandamide, but a putative competitive inhibitor of the TRPV1. Four additional inactive compounds (N-isobutyl-4,5-epoxy-2E-decadienamide, geranylpsoralen, 8-(7',8'-epoxygeranyloxy)psoralen, and xanthotoxol) were also co-purified with pellitorine. Their structures were established by extensive 1D- and 2D-NMR spectroscopic analysis.
H- and C NMR determination of the chemical structure revealed it to be pellitorine, (2E,4E)-N-(2-methylpropyl)deca-2,4-dienamide, which can compete structurally with algesics released in inflammation. In contrast to previous isolates from Evodia species, pellitorine blocked capsaicin-evoked Ca uptake with an IC of 154 µg/ml (0.69 mM/l). N-Isobutyl-4,5-epoxy-2E-decadienamide and geranylpsoralen, 8-(7',8'-epoxygeranyloxy)psoralen, and xanthotoxol did not affect the TRPV1.
This is the first evidence that pellitorine, an aliphatic alkylamide analogue of capsaicin, can serve as an antagonist of the TRPV1 and may inhibit exovanilloid-induced pain.
瞬时受体电位香草酸 1 型（TRPV1）在周围神经系统中传递有害热和炎症疼痛信号。从大戟属植物瑞香素的临床试验成功地针对癌症疼痛管理中的 TRPV1，并朝着新的选择性止痛药状态发展，这进一步验证了该靶点在药物发现工作中的作用。在传统医学中使用了数百年的吴茱萸属植物是不同 TRPV1 激动剂的公认来源，但尚未报道有任何拮抗剂。
假设/目的：在寻找止痛药先导化合物时，我们首次注意到 Tetradium daniellii（Benn.）T.G. Hartley（同义词 Euodia hupehensis Dode）的新鲜果实具有 TRPV1 拮抗剂活性。
通过提取和纯化方法与功能性 TRPV1 特异性 Ca 摄取测定（生物活性指导的分级分离/分离/纯化）相结合；我们分离出一种新的止痛候选物，它是辣椒素外香草酸和内香草酸（如大麻素）的远结构同源物，但却是 TRPV1 的一种假定竞争性抑制剂。还与pelitorine 共纯化了另外四种无活性化合物（N-异丁基-4,5-环氧-2E-癸二烯酰胺、香叶基补骨脂素、8-（7',8'-环氧香叶基）补骨脂素和花椒毒素）。通过广泛的 1D 和 2D-NMR 光谱分析确定了它们的结构。
通过 H 和 C NMR 确定化学结构表明它是 pelitorine，（2E,4E）-N-（2-甲基丙基）癸-2,4-二烯酰胺，它可以在结构上与炎症中释放的致痛剂竞争。与以前从吴茱萸属植物中分离出的化合物不同，pelitorine 以 154µg/ml（0.69mM/l）的 IC 阻断辣椒素诱导的 Ca 摄取。N-异丁基-4,5-环氧-2E-癸二烯酰胺、香叶基补骨脂素、8-（7',8'-环氧香叶基）补骨脂素和花椒毒素对 TRPV1 没有影响。
这是第一个证据表明，辣椒素的脂肪族烷基酰胺类似物 pelitorine 可以作为 TRPV1 的拮抗剂，并可能抑制外香草酸诱导的疼痛。
