Takayama Kentaro, Mori Kenji, Sohma Yuko, Taketa Koji, Taguchi Akihiro, Yakushiji Fumika, Minamino Naoto, Miyazato Mikiya, Kangawa Kenji, Hayashi Yoshio
Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences , 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
Department of Biochemistry and Department of Molecular Pharmacology, National Cerebral and Cardiovascular Center Research Institute , 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
ACS Med Chem Lett. 2015 Jan 28;6(3):302-7. doi: 10.1021/ml500494j. eCollection 2015 Mar 12.
Neuromedin U (NMU) and S (NMS) display various physiological activities, including an anorexigenic effect, and share a common C-terminal heptapeptide-amide sequence that is necessary to activate two NMU receptors (NMUR1 and NMUR2). On the basis of this knowledge, we recently developed hexapeptide agonists 2 and 3, which are highly selective to human NMUR1 and NMUR2, respectively. However, the agonists are still less potent than the endogenous ligand, hNMU. Therefore, we performed an additional structure-activity relationship study, which led to the identification of the more potent hexapeptide 5d that exhibits similar NMUR1-agonistic activity as compared to hNMU. Additionally, we studied the stability of synthesized agonists, including 5d, in rat serum, and identified two major biodegradation sites: Phe(2)-Arg(3) and Arg(5)-Asn(6). The latter was more predominantly cleaved than the former. Moreover, substitution with 4-fluorophenylalanine, as in 5d, enhanced the metabolic stability at Phe(2)-Arg(3). These results provide important information to guide the development of practical hNMU agonists.
神经介素U（NMU）和神经介素S（NMS）具有多种生理活性，包括厌食作用，并且共享一个共同的C末端七肽酰胺序列，该序列是激活两种NMU受体（NMUR1和NMUR2）所必需的。基于这一认识，我们最近开发了六肽激动剂2和3，它们分别对人NMUR1和NMUR2具有高度选择性。然而，这些激动剂的效力仍低于内源性配体hNMU。因此，我们进行了一项额外的构效关系研究，从而鉴定出了效力更强的六肽5d，其表现出与hNMU相似的NMUR1激动活性。此外，我们研究了包括5d在内的合成激动剂在大鼠血清中的稳定性，并确定了两个主要的生物降解位点：苯丙氨酸（2）-精氨酸（3）和精氨酸（5）-天冬酰胺（6）。后者比前者更易被切割。此外，如果像在5d中那样用4-氟苯丙氨酸进行取代，则会增强苯丙氨酸（2）-精氨酸（3）处的代谢稳定性。这些结果为指导实用的hNMU激动剂的开发提供了重要信息。
