A potent neuromedin U receptor 2-selective alkylated peptide.

Naoki Nishizawa, Yoko Kanematsu-Yamaki, Masaaki Funata, Hiroaki Nagai, Ayako Shimizu, Hisashi Fujita, Junichi Sakamoto, Shiro Takekawa, Taiji Asami

Bioorganic & medicinal chemistry letters 2017 Oct 15

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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 [αMePhe19, Nle21, and Arg(Me)24] 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. Copyright © 2017 Elsevier Ltd. All rights reserved.

Citation

Naoki Nishizawa, Yoko Kanematsu-Yamaki, Masaaki Funata, Hiroaki Nagai, Ayako Shimizu, Hisashi Fujita, Junichi Sakamoto, Shiro Takekawa, Taiji Asami. A potent neuromedin U receptor 2-selective alkylated peptide. Bioorganic & medicinal chemistry letters. 2017 Oct 15;27(20):4626-4629