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Discovery of potent hexapeptide agonists to human Neuromedin U receptor 1 and identification of their serum metabolites

ACS Medicinal Chemistry Letters, ISSN: 1948-5875, Vol: 6, Issue: 3, Page: 302-307
2015
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Article Description

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-Arg and Arg-Asn. The latter was more predominantly cleaved than the former. Moreover, substitution with 4-fluorophenylalanine, as in 5d, enhanced the metabolic stability at Phe-Arg. These results provide important information to guide the development of practical hNMU agonists.

Bibliographic Details

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

American Chemical Society (ACS)

Biochemistry, Genetics and Molecular Biology; Pharmacology, Toxicology and Pharmaceutics; Chemistry

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