Sefler A M, He J X, Sawyer T K, Holub K E, Omecinsky D O, Reily M D, Thanabal V, Akunne H C, Cody W L
Department of Chemistry, Parke-Davis Pharmaceutical Research, Division of the Warner-Lambert Company, Ann Arbor, Michigan 48106.
J Med Chem. 1995 Jan 20;38(2):249-57. doi: 10.1021/jm00002a006.
Neurotensin (NT) is a linear tridecapeptide with a broad range of central and peripheral pharmacological effects. The C-terminal hexapeptide of NT (NT8-13) has been shown to possess similar properties to NT itself, and in fact, an analogue of NT8-13 (N alpha MeArg8-Lys-Pro-Trp-Tle-Leu13, Tle = tert-leucine) has been reported to possess central activity after peripheral administration. Cyclic derivatives of this hexapeptide were synthesized by a combination of solution and solid-phase peptide synthetic methodologies, and several analogues had low nanomolar binding affinity for the NT receptor. In particular, cyclo[Arg-Lys-Pro-Trp-Glu]-Leu (cyclized between the alpha amine of Arg and the gamma carboxylate of Glu) possessed 16 nM NT receptor affinity and was determined to be an agonist in vitro. 1H-NMR and 13C-edited 1H-NMR spectroscopy were performed on this and related cyclic analogues to help identify structural properties which may be important for receptor recognition. These cyclic peptides represent novel molecular probes to further investigate NT receptor pharmacology, as well as to advance our understanding of the structure-conformation relationships of NT and to help establish a working basis for additional pharmacophore mapping studies.
神经降压素（NT）是一种线性十三肽，具有广泛的中枢和外周药理作用。NT的C末端六肽（NT8 - 13）已被证明具有与NT本身相似的性质，事实上，据报道NT8 - 13的一种类似物（NαMeArg8 - Lys - Pro - Trp - Tle - Leu13，Tle = 叔亮氨酸）在外周给药后具有中枢活性。通过溶液和固相肽合成方法相结合合成了这种六肽的环化衍生物，并且几种类似物对NT受体具有低纳摩尔结合亲和力。特别地，环[Arg - Lys - Pro - Trp - Glu] - Leu（在Arg的α胺和Glu的γ羧酸盐之间环化）具有16 nM的NT受体亲和力，并被确定为体外激动剂。对该环化类似物及相关环化类似物进行了1H - NMR和13C编辑的1H - NMR光谱分析，以帮助确定对于受体识别可能重要的结构性质。这些环化肽代表了新型分子探针，可进一步研究NT受体药理学，以及加深我们对NT结构 - 构象关系的理解，并有助于为额外的药效团图谱研究建立工作基础。
