Horwell D C, Howson W, Ratcliffe G S, Willems H M
Parke-Davis Neuroscience Research Centre, Addenbrookes Hospital Site, Cambridge, U.K.
Bioorg Med Chem. 1996 Jan;4(1):33-42. doi: 10.1016/0968-0896(95)00169-7.
The design and synthesis of conformationally constrained, nonpeptide templates (1,1,6-trisubstituted indanes) which allow the incorporation of two adjacent amino acid side chains, plus a third binding group in an orientation similar to that found in alpha-helices are reported. Six racemic and two homochiral Phe-Phe and Trp-Phe mimetics were synthesised and evaluated in tachykinin receptor binding assays as molecular probes for the binding conformation of the endogenous peptides. Several were found to bind with micromolar affinity to the NK1 and/or NK3 receptor. The conformation of one of the homochiral indanes, (1R)-N-((S)-1-hydroxymethylbenzyl)-1,6-dibenzylindan-1-carbo xamide, was analysed by X-ray crystallography and was found to be in an alpha-helix conformation.
报道了构象受限的非肽模板（1,1,6-三取代茚满）的设计与合成，该模板允许引入两个相邻的氨基酸侧链，外加一个与α-螺旋中发现的取向相似的第三结合基团。合成了六个外消旋体以及两个纯手性的苯丙氨酸-苯丙氨酸和色氨酸-苯丙氨酸模拟物，并在速激肽受体结合试验中作为内源性肽结合构象的分子探针进行了评估。发现其中几种与NK1和/或NK3受体以微摩尔亲和力结合。通过X射线晶体学分析了其中一种纯手性茚满，即(1R)-N-((S)-1-羟甲基苄基)-1,6-二苄基茚满-1-甲酰胺的构象，发现其处于α-螺旋构象。
