Discovery of Selective Hexapeptide Agonists to Human Neuromedin U Receptors Types 1 and 2
Discovery of Selective Hexapeptide Agonists to Human Neuromedin U Receptors Types 1 and 2
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DOI：
10.1021/jm500599s
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发表时间：
2014-08-14
影响因子：
7.3
通讯作者：
Hayashi, Yoshio
中科院分区：
文献类型：
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作者：
Takayama, Kentaro;Mori, Kenji;Hayashi, Yoshio
神经介肽U（Neuromedin U，NMU）是哺乳动物中具有共同的C-末端七肽序列（FLFRPRN-酰胺，1a）的生物活性肽，其负责受体活化，即NMU受体1型（NMU 1）和2型（NMU 2）。在NMU的各种生理作用中，最近在用于治疗肥胖的药物发现努力中引起了注意。尽管已经报道了几种结构活性关系（SAR）研究，但尚未公开受体选择性小肽激动剂。本文描述了Ia衍生的肽衍生物的SAR研究。我们最初在钙动员试验中用瞬时表达受体的细胞筛选了人NMUR 1和NMUR 2选择性肽。然后，我们用受体的稳定表达系统进行了精确的测定，并因此发现了对每个相应受体具有选择性激动剂活性的六肽8d和6 b。六肽6 b，选择性激活NMUR 2而没有显着的NMUR 1激活，应该有助于开发促凋亡药物，以及推进NMU相关的内分泌研究。
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 la-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.