Synthesis and Biological Activity of Human Neuropeptide S Analogues Modified in Position 2

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• 作者：Valeria Camarda ; Claudio Trapella ; Girolamo Calo′ ; Remo Guerrini ; Anna Rizzi ; Chiara Ruzza ; Stella Fiorini ; Erika Marzola ; Rainer K. Reinscheid ; Domenico Regoli ; Severo Salvadori
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：February 14, 2008
• 年：2008
• 卷：51
• 期：3
• 页码：655 - 658
• 全文大小：84K
• 年卷期：v.51,no.3(February 14, 2008)
• ISSN：1520-4804

文摘

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 Phe²-Arg³-Asn⁴ of the peptide is crucial for biological activity. Here we report on a focused structure–activity study of Phe² 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-Ala²]hNPS behaved as a partial agonist.