title: Discovery of potent hexapeptide agonists to human neuromedin u receptor 1 and identification of their serum metabolites.
abstract: 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.
authors: Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences , 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
authors: Kentaro
authors: K
authors: Takayama
authors: Department of Biochemistry and Department of Molecular Pharmacology, National Cerebral and Cardiovascular Center Research Institute , 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
authors: Kenji
authors: K
authors: Mori
authors: Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences , 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
authors: Yuko
authors: Y
authors: Sohma
authors: Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences , 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
authors: Koji
authors: K
authors: Taketa
authors: Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences , 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
authors: Akihiro
authors: A
authors: Taguchi
authors: Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences , 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
authors: Fumika
authors: F
authors: Yakushiji
authors: Department of Biochemistry and Department of Molecular Pharmacology, National Cerebral and Cardiovascular Center Research Institute , 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
authors: Naoto
authors: N
authors: Minamino
authors: Department of Biochemistry and Department of Molecular Pharmacology, National Cerebral and Cardiovascular Center Research Institute , 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
authors: Mikiya
authors: M
authors: Miyazato
authors: Department of Biochemistry and Department of Molecular Pharmacology, National Cerebral and Cardiovascular Center Research Institute , 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
authors: Kenji
authors: K
authors: Kangawa
authors: Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences , 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
authors: Yoshio
authors: Y
authors: Hayashi
keywords: Agonist; biodegradation site; neuromedin U; neuromedin U receptor; peptide