Walpole C S, Bevan S, Bloomfield G, Breckenridge R, James I F, Ritchie T, Szallasi A, Winter J, Wrigglesworth R
Sandoz Institute for Medical Research, London, UK.
J Med Chem. 1996 Jul 19;39(15):2939-52. doi: 10.1021/jm960139d.
Structure-activity relationships in analogues of the irritant natural product capsaicin have previously been rationalized by subdivision of the molecule into three structural regions (A,B, and C). The hypothesis that resiniferatoxin (RTX), which is a high-potency ligand for the same receptor and which has superficial structural similarities with capsaicin, could be analogously subdivided has been investigated. The effects of making parallel changes in the two structural series have been studied in a cellular functional assay which is predictive of analgesic activity. Parallel structural changes in the two series lead to markedly different consequences on biological activity; the 3- and 4-position aryl substituents (corresponding to the capsaicin 'A-region') which are strictly required for activity in capsaicin analogues are not important in RTX analogues. The homovanillyl C-20 ester group in RTX (corresponding to the capsaicin 'B-region') is more potent than the corresponding amide, in contrast to the capsaicin analogues. Structural variations to the diterpene moiety suggest that the functionalized 5-membered diterpene ring of RTX is an important structural determinant for high potency. Modeling studies indicate that the 3D position of the alpha-hydroxy ketone moiety in the 5-membered ring is markedly different in the phorbol (inactive) analogues and RTX (active) series. This difference appears to be due to the influence of the strained ortho ester group in RTX, which acts as a local conformational constraint. The reduced activity of an analogue substituted in this region and the inactivity of a simplified analogue in which this unit is entirely removed support this conclusion.
刺激性天然产物辣椒素类似物的构效关系先前已通过将分子细分为三个结构区域（A、B和C）来进行合理化解释。树脂毒素（RTX）是同一受体的高效配体，与辣椒素在表面结构上有相似之处，关于其是否可类似地细分这一假设已得到研究。在一项可预测镇痛活性的细胞功能试验中，研究了在两个结构系列中进行平行变化的影响。两个系列中的平行结构变化对生物活性产生了明显不同的影响；辣椒素类似物中活性严格要求的3位和4位芳基取代基（对应于辣椒素“A区域”）在RTX类似物中并不重要。与辣椒素类似物相反，RTX中的高香草基C - 20酯基（对应于辣椒素“B区域”）比相应的酰胺更有效。对二萜部分的结构变化表明，RTX的官能化五元二萜环是高效力的重要结构决定因素。建模研究表明，在佛波醇（无活性）类似物和RTX（活性）系列中，五元环中α - 羟基酮部分的三维位置明显不同。这种差异似乎是由于RTX中受张力的原酸酯基团的影响，该基团起到局部构象限制的作用。在该区域取代的类似物活性降低以及完全去除该单元的简化类似物无活性支持了这一结论。
