Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Università del Piemonte Orientale, Via Bovio 6, 28100 Novara, Italy.
Bioorg Med Chem Lett. 2010 Jan 1;20(1):97-9. doi: 10.1016/j.bmcl.2009.11.035. Epub 2009 Nov 14.
The side chain benzylic methylene is a critical element for the vanilloid activity of resiniferatoxin (2a, RTX), and introduction of branching, oxygen functions, or isosteric substitution at this center proved detrimental, with a decrease of potency of 2-3 orders of magnitude compared to the natural product. Conversely, only a modest erosion of activity was observed upon alpha-methylation and alpha-methylenation of the side chain. Surprisingly, introduction of an iodine atom in the guaiacyl moiety of the oxygen isoster 2h led to an unexpected and remarkable (>1000-fold) increase of potency, affording 2i, a compound that outperforms RTX in terms of vanilloid agonism and represents the first one-digit picomolar ligand of a TRP channel discovered to date.
侧链苄叉亚甲基是树脂毒素 (2a, RTX) 香草素活性的关键因素，在该中心引入支链、含氧官能团或等排取代基被证明是有害的，与天然产物相比，效力降低了 2-3 个数量级。相反，侧链的α-甲基化和α-亚甲基化仅观察到活性适度降低。令人惊讶的是，在氧等排体 2h 的愈创木基部分引入碘原子导致活性出人意料地显著（>1000 倍）增加，得到 2i，这是一种化合物，在香草素激动剂方面优于 RTX，是迄今为止发现的第一个 TRPV 通道的一位数皮摩尔配体。
