Camarda Valeria, Trapella Claudio, Calo Girolamo, Guerrini Remo, Rizzi Anna, Ruzza Chiara, Fiorini Stella, Marzola Erika, Reinscheid Rainer K, Regoli Domenico, Salvadori Severo
Department of Experimental and Clinical Medicine, Section of Pharmacology and Italian Institute of Neuroscience, University of Ferrara, via Fossato di Mortara 19, Ferrara, Italy.
J Med Chem. 2008 Feb 14;51(3):655-8. doi: 10.1021/jm701204n. Epub 2008 Jan 9.
Neuropeptide S (NPS) has been identified as the endogenous ligand of a previously orphan receptor now named NPSR. Previous studies demonstrated that the N-terminal sequence Phe (2)-Arg(3)-Asn(4) of the peptide is crucial for biological activity. Here we report on a focused structure-activity study of Phe(2) which has been replaced with a series of coded and noncoded amino acids. Thirty-one human NPS analogues were synthesized and pharmacologically tested for intracellular calcium mobilization by using HEK293 cells stably expressing the mouse NPSR. The results of this study demonstrated the following NPS position 2 structure-activity features: (i) lipophilicity but not aromaticity is crucial, (ii) both the size of the chemical moiety and its distance from the peptide backbone are important for biological activity, and (iii) this position plays a role in both receptor binding and activation, since [4,4'-biphenyl-Ala(2)]hNPS behaved as a partial agonist.
神经肽S（NPS）已被确定为一种先前未明确配体的受体（现称为NPSR）的内源性配体。先前的研究表明，该肽的N端序列苯丙氨酸（2）-精氨酸（3）-天冬酰胺（4）对生物活性至关重要。在此，我们报告了一项针对苯丙氨酸（2）的重点构效关系研究，该位点已被一系列编码和非编码氨基酸取代。合成了31种人NPS类似物，并使用稳定表达小鼠NPSR的HEK293细胞对其进行细胞内钙动员的药理学测试。本研究结果表明了以下NPS第2位的构效关系特征：（i）亲脂性而非芳香性至关重要；（ii）化学基团的大小及其与肽主链的距离对生物活性均很重要；（iii）该位点在受体结合和激活中均起作用，因为[4,4'-联苯-丙氨酸（2）]人NPS表现为部分激动剂。
