A chemically stable peptide agonist to neuromedin U receptor type 2

Kentaro Takayama; Kenji Mori; Akiko Tanaka; Yu Sasaki; Yuko Sohma; Akihiro Taguchi; Atsuhiko Taniguchi; Toshiyasu Sakane; Akira Yamamoto; Mikiya Miyazato; Naoto Minamino; Kenji Kangawa; Yoshio Hayashi

doi:10.1016/j.bmc.2020.115454

A chemically stable peptide agonist to neuromedin U receptor type 2

Bioorg Med Chem. 2020 May 15;28(10):115454. doi: 10.1016/j.bmc.2020.115454. Epub 2020 Mar 22.

Authors

Affiliations

¹ Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan; Department of Environmental Biochemistry, Kyoto Pharmaceutical University, 5 Misasaginakauchi-cho, Yamashina, Kyoto 607-8414, Japan. Electronic address: ktaka59@mb.kyoto-phu.ac.jp.
² Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe-Shimmachi, Suita, Osaka 564-8565, Japan.
³ Laboratory of Pharmaceutical Technology, Kobe Pharmaceutical University, 4-19-1 Motoyamakitamachi, Higashinada, Kobe, Hyogo 658-8558, Japan.
⁴ Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
⁵ Department of Biopharmaceutics, Kyoto Pharmaceutical University, 5 Misasaginakauchi-cho, Yamashina, Kyoto 607-8414, Japan.
⁶ Omics Research Center, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita, Osaka 564-8565, Japan.
⁷ Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan. Electronic address: yhayashi@toyaku.ac.jp.

PMID: 32247748
DOI: 10.1016/j.bmc.2020.115454

Abstract

Neuromedin U (NMU) is a peptide with appetite suppressive activity and other physiological activities via activation of the NMU receptors NMUR1 and NMUR2. In 2014, we reported the first NMUR2 selective agonist, 3-cyclohexylpropionyl-Leu-Leu-Dap-Pro-Arg-Asn-NH₂ (CPN-116). However, we found that CPN-116 in phosphate buffer is unstable because of N^α-to-N^β acyl migration at the Dap residue. In this study, the chemical stability of CPN-116 was evaluated under various conditions, and it was found to be relatively stable in buffers such as HEPES and MES. We also performed a structure-activity relationship study to obtain an NMUR2-selective agonist with improved chemical stability. Consequently, CPN-219 bearing a Dab residue in place of Dap emerged as a next-generation hexapeptidic NMUR2 agonist.

Keywords: Agonist; Chemical stability; Good’s buffer; Neuromedin U receptor type 2; Peptide.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Dose-Response Relationship, Drug
Hydrogen-Ion Concentration
Mice
Protein Conformation
Receptors, Neurotransmitter / agonists*
Structure-Activity Relationship

Substances

Receptors, Neurotransmitter
neuromedin U receptor