Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich Alexander University, Schuhstraße 19, 91052 Erlangen, Germany.
ChemMedChem. 2013 May;8(5):772-8. doi: 10.1002/cmdc.201300054. Epub 2013 Mar 26.
To investigate the binding mode and structure-activity relationships (SARs) of selective neurotensin receptor 2 (NTS2) ligands, novel peptide-peptoid hybrids that simulate the function of the endogenous ligand were developed. Starting from our recently described NTS2 ligands of type 1, structural variants of type 2 and the metabolically stable analogues 3 a,b were developed. Replacement of the proline unit by a collection of structural surrogates and evaluation of the respective molecular probes for NTS2 affinity and selectivity indicated similar SARs as described for NT(8-13) derivatives bound to the subtype NTS1. Peptide-peptoid hybrids 2 d, 3 a,b showed substantial NTS2 binding affinity (Ki =8.1-16 nM) and 2400-8600-fold selectivity over NTS1. The thiazolidine derivative 3 b showed metabolic stability over 32 h in a serum degradation assay. In an inositol phosphate accumulation assay, the neurotensin mimetics 3 a and 3 b displayed an inhibition of constitutive activity exceeding 1.7-2.0 times the activity of NT(8-13). The fluorinated derivative 3 a could afford attractive opportunities to detect NTS2 by (19) F magnetic resonance imaging.
为了研究选择性神经降压素受体 2（NTS2）配体的结合模式和构效关系（SARs），开发了模拟内源性配体功能的新型肽-肽混合体。从我们最近描述的 1 型 NTS2 配体开始，开发了 2 型结构变体和代谢稳定的类似物 3a,b。用一系列结构替代物替代脯氨酸单元，并评估各自的 NTS2 亲和力和选择性的分子探针，结果表明与结合亚型 NTS1 的 NT（8-13）衍生物类似的 SAR。肽-肽混合体 2d、3a,b 表现出相当大的 NTS2 结合亲和力（Ki=8.1-16 nM）和对 NTS1 的 2400-8600 倍选择性。噻唑烷衍生物 3b 在血清降解测定中具有超过 32 小时的代谢稳定性。在肌醇磷酸盐积累测定中，神经降压素模拟物 3a 和 3b 显示出超过 NT（8-13）活性 1.7-2.0 倍的组成性活性抑制。氟化衍生物 3a 可以通过（19）F 磁共振成像提供检测 NTS2 的有吸引力的机会。
