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Discovery of Selective Hexapeptide Agonists to Human Neuromedin U Receptors Types 1 and 2

Kentaro Takayama, Kenji Mori, Koji Taketa, Akihiro Taguchi, Fumika Yakushiji, Naoto Minamino, Mikiya Miyazato, Kenji Kangawa, and Yoshio Hayashi, J. Med. Chem., Articles ASAP (As Soon As Publishable); Publication Date (Web): July 7, 2014 (Article)

Neuromedin U (NMU) are bioactive peptides with a common C-terminal heptapeptide sequence (FLFRPRN-amide, 1a) among mammals, which is responsible for receptor activation, namely NMU receptor types 1 (NMUR1) and 2 (NMUR2). Among the various physiological actions of NMU, the anorexigenic effect has recently attracted attention in drug discovery efforts for treating obesity. Although several structure–activity relationship (SAR) studies have been reported, receptor-selective small peptide agonists have yet to be disclosed. Herein a SAR study of 1a-derived peptide derivatives is described. We initially screened both human NMUR1- and NMUR2-selective peptides in calcium-mobilization assays with cells transiently expressing receptors. Then we performed a precise assay with a stable expression system of receptors and consequently discovered  hexapeptides 8d and 6b possessing selective agonist activity toward each respective receptor. Hexapeptide 6b, which selectively activates NMUR2 without significant NMUR1 activation, should aid in the development of anorexigenic drugs as well as advance NMU-related endocrinological research.