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.
Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe-Shimmachi, Suita, Osaka 564-8565, Japan.
Bioorg Med Chem. 2020 May 15;28(10):115454. doi: 10.1016/j.bmc.2020.115454. Epub 2020 Mar 22.
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-NH (CPN-116). However, we found that CPN-116 in phosphate buffer is unstable because of N-to-N 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.
神经调节素 U（NMU）是一种具有抑制食欲作用的肽，通过 NMU 受体 NMUR1 和 NMUR2 的激活具有其他生理活性。2014 年，我们报道了第一个 NMUR2 选择性激动剂，3-环己基丙酰基-Leu-Leu-Dap-Pro-Arg-Asn-NH（CPN-116）。然而，我们发现 CPN-116 在磷酸盐缓冲液中由于 Dap 残基的 N 到 N 酰基迁移而不稳定。在这项研究中，评估了 CPN-116 在各种条件下的化学稳定性，结果发现它在 HEPES 和 MES 等缓冲液中相对稳定。我们还进行了构效关系研究，以获得一种具有改善化学稳定性的 NMUR2 选择性激动剂。因此，用 Dab 取代 Dap 的 CPN-219 成为新一代六肽 NMUR2 激动剂。
