Discovery of Potent Hexapeptide Agonists to Human Neuromedin U Receptor 1 and Identification of Their Serum Metabolites

作者：Takayama Kentaro; Mori Kenji; Sohma Yuko; Taketa Koji; Taguchi Akihiro; Yakushiji Fumika; Minamino Naoto; Miyazato Mikiya; Kangawa Kenji; Hayashi Yoshio^*

来源：ACS Medicinal Chemistry Letters, 2015, 6(3): 302-307.

DOI：10.1021/ml500494j

• Agonist
• biodegradation site
• neuromedin U
• neuromedin U receptor
• peptide

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.

• 出版日期2015-3