Discovery of Selective HexapeptideAgonists to HumanNeuromedin U Receptors Types 1 and 2.

Neuromedin U (NMU) are bioactivepeptides with a common C-terminalheptapeptide sequence (FLFRPRN-amide, 1a) among mammals,which is responsible for receptor activation, namely NMU receptortypes 1 (NMUR1) and 2 (NMUR2). Among the various physiological actionsof NMU, the anorexigenic effect has recently attracted attention indrug discovery efforts for treating obesity. Although several structure–activityrelationship (SAR) studies have been reported, receptor-selectivesmall peptide agonists have yet to be disclosed. Herein a SAR studyof 1a-derived peptide derivatives is described. We initiallyscreened both human NMUR1- and NMUR2-selective peptides in calcium-mobilizationassays with cells transiently expressing receptors. Then we performeda precise assay with a stable expression system of receptors and consequentlydiscovered hexapeptides 8dand 6bpossessingselective agonist activity toward each respective receptor. Hexapeptide 6b, which selectively activates NMUR2 without significantNMUR1 activation, should aid in the development of anorexigenic drugsas well as advance NMU-related endocrinological research. [ABSTRACT FROM AUTHOR]