German Nadezhda A, Decker Ann M, Gilmour Brian P, Thomas Brian F, Zhang Yanan
Research Triangle Institute, Research Triangle Park, NC 27709.
ACS Med Chem Lett. 2013 Dec 12;4(12):1224-1227. doi: 10.1021/ml400333a.
Orexin receptors are involved in many processes including energy homeostasis, wake/sleep cycle, metabolism and reward. Development of potent and selective ligands is an essential step for defining the mechanism(s) underlying such critical processes. The goal of this study was to further investigate the structure-activity relationships of these peptides and to identify truncated form of the orexin peptides active at OX. Truncation studies have led to OXA (17-33) as the shortest active peptide known to date with a 23-fold selectivity for OX over OX. Alanine, D-amino acid and proline scans have highlighted the particular importance of Tyr, Leu, Asn and His for agonist properties of OXA(17-33). The conformation of the C-terminus might also be a defining factor in agonist activity and selectivity of the orexin peptides for the OX receptor.
食欲素受体参与包括能量平衡、清醒/睡眠周期、新陈代谢和奖赏等许多过程。开发强效且选择性的配体是确定这些关键过程潜在机制的重要一步。本研究的目的是进一步研究这些肽的构效关系，并鉴定在OX受体上具有活性的食欲素肽的截短形式。截短研究已得到OXA(17 - 33)，它是迄今为止已知的最短的活性肽，对OX受体的选择性比对OX受体高23倍。丙氨酸、D - 氨基酸和脯氨酸扫描突出了Tyr、Leu、Asn和His对OXA(17 - 33)激动剂特性的特别重要性。C末端的构象也可能是食欲素肽对OX受体激动剂活性和选择性的决定性因素。
