Nishizawa Naoki, Kanematsu-Yamaki Yoko, Funata Masaaki, Nagai Hiroaki, Shimizu Ayako, Fujita Hisashi, Sakamoto Junichi, Takekawa Shiro, Asami Taiji
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, Fujisawa 251-8555, Japan.
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, Fujisawa 251-8555, Japan.
Bioorg Med Chem Lett. 2017 Oct 15;27(20):4626-4629. doi: 10.1016/j.bmcl.2017.09.019. Epub 2017 Sep 9.
Neuromedin U (NMU) mediates various physiological functions via NMUR1 and NMUR2 receptors. NMUR2 has been considered a promising treatment option for diabetes and obesity. Although NMU-8, a shorter peptide, has potent agonist activity for both receptors, it is metabolically unstable. Therefore, NMU-8 analogs modified with long-chain alkyl moieties via a linker were synthesized. An octadecanoyl analog (17) with amino acid substitutions [αMePhe, Nle, and Arg(Me)] and a linker [Tra-γGlu-PEG(2)] dramatically increased NMUR2 selectivity, with retention of high agonist activity. Subcutaneous administration of 17 induced anorectic activity in C57BL/6J mice. Owing to its high metabolic stability, 17 would be useful in clarifying the physiological role and therapeutic application of NMU.
神经介素U（NMU）通过NMU受体1（NMUR1）和NMU受体2（NMUR2）介导多种生理功能。NMUR2被认为是治疗糖尿病和肥胖症的一个有前景的选择。尽管较短的肽NMU-8对这两种受体都具有强大的激动剂活性，但它在代谢上不稳定。因此，合成了通过连接子与长链烷基部分修饰的NMU-8类似物。一种具有氨基酸取代[α-甲基苯丙氨酸、正亮氨酸和精氨酸（甲基）]和连接子[三肽-γ-谷氨酸-聚乙二醇（2）]的十八烷酰类似物（17）显著提高了NMUR2的选择性，并保留了高激动剂活性。皮下注射17可诱导C57BL/6J小鼠产生厌食活性。由于其高代谢稳定性，17将有助于阐明NMU的生理作用和治疗应用。
