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.
Kentaro Takayama  1 ,  Kenji Mori  2 ,  Akiko Tanaka  3 ,  Yu Sasaki  4 ,  Yuko Sohma  4 ,  Akihiro Taguchi  4 ,  Atsuhiko Taniguchi  4 ,  Toshiyasu Sakane  3 ,  Akira Yamamoto  5 ,  Mikiya Miyazato  2 ,  Naoto Minamino  6 ,  Kenji Kangawa  2 ,  Yoshio Hayashi  7
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: [email protected].
  • 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: [email protected].
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 Nα-to-Nβ 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.
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