Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich Alexander University, Schuhstraße 19, 91052 Erlangen, Germany.
ChemMedChem. 2013 Jan;8(1):75-81. doi: 10.1002/cmdc.201200376. Epub 2012 Oct 24.
Subtype-selective neurotensin receptor 2 (NTS2) ligands can be used as molecular probes to investigate the physiological role of neurotensinergic systems and serve as lead compounds to initiate the development of drugs for the treatment of tonic pain. Starting from our recently described NTS2 ligand 1, structural variants of type 2 were synthesized to further improve binding affinity and selectivity to gain metabolic stability. The peptide-peptoid hybrid 2 b showed excellent NTS2 binding affinity (K(i) =2.8 nM) and 22 000-fold selectivity over NTS1, as well as metabolic stability over 32 h in a serum degradation assay. Employing a MAPK-driven luciferase reporter gene assay and an IP accumulation assay, the neurotensin mimetic 2 b displayed respective inhibitions of constitutive activity exceeding 4.3- and 3.9-fold that of the inverse agonist activity of the endogenous ligand neurotensin.
亚型选择性神经降压素受体 2（NTS2）配体可用作分子探针，以研究神经降压素能系统的生理作用，并作为先导化合物，启动治疗张力性疼痛药物的开发。从我们最近描述的 NTS2 配体 1 出发，合成了 2 型结构变体，以进一步提高结合亲和力和选择性，获得代谢稳定性。肽-肽拟似物 2b 表现出优异的 NTS2 结合亲和力（K(i)=2.8nM）和对 NTS1 的 22000 倍选择性，以及在血清降解测定中超过 32 小时的代谢稳定性。通过 MAPK 驱动的荧光素酶报告基因测定和 IP 积累测定，神经降压素类似物 2b 对组成型活性的抑制作用分别超过内源性配体神经降压素的反向激动剂活性的 4.3-和 3.9 倍。
