Walpole C S, Wrigglesworth R, Bevan S, Campbell E A, Dray A, James I F, Masdin K J, Perkins M N, Winter J
Sandoz Institute for Medical Research, Gower Place, London, England.
J Med Chem. 1993 Aug 6;36(16):2373-80. doi: 10.1021/jm00068a015.
A series of compounds incorporating replacements for the amide bond "B-region" moiety of capsaicin have been synthesized, including vanillylamides and esters, homovanillic acid amides and esters, ureas, and thioureas. These have been tested in an in vitro assay for agonism (45Ca2+ influx into dorsal root ganglia neurones), which is predictive of analgesic activity, to investigate the requirements in this region of capsaicin for activity. N-(4-Hydroxy-3-methoxybenzyl)-N'-octylthiourea (14a) emerged as the most potent analogue (EC50 = 0.06 microM). An operational model based on multiple hydrogen-bonding interactions is proposed to explain the structure-activity profile observed. In combination with studies on the other regions of the capsaicin molecule these results describe a picture of the molecular interactions of capsaicin with its putative receptor.
已合成了一系列包含辣椒素酰胺键“B区域”部分替代物的化合物，包括香草酰胺和酯、高香草酸酰胺和酯、脲以及硫脲。这些化合物已在体外激动试验（45Ca2+流入背根神经节神经元）中进行了测试，该试验可预测镇痛活性，以研究辣椒素该区域的活性要求。N-(4-羟基-3-甲氧基苄基)-N'-辛基硫脲（14a）是最有效的类似物（EC50 = 0.06 microM）。提出了一个基于多重氢键相互作用的操作模型来解释所观察到的构效关系。结合对辣椒素分子其他区域的研究，这些结果描绘了辣椒素与其假定受体的分子相互作用情况。
