Structure-activity relationship study on senktide for development of novel potent neurokinin-3 receptor selective agonists.
Structure-activity relationship study on senktide for development of novel potent neurokinin-3 receptor selective agonists.
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senktide 的构效关系研究，用于开发新型强效神经激肽 3 受体选择性激动剂。
DOI：
10.1039/c4md00514g
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Fujii N.
中科院分区：
文献类型：
--
作者：
Misu R;Yamamoto K;Yamada A;Noguchi T;Ohno H;Yamamura T;Okamura H;Matsuda F;Ohkura S;Oishi S;Fujii N.
神经激肽B（NKB）通过激活同源神经激肽-3受体（NK 3 R）调节下丘脑中促性腺激素释放激素（GnRH）的分泌。NKB及其衍生物对促性腺激素分泌的刺激作用可潜在地用于开发用于生殖功能障碍的新型调节剂和治疗剂。在这里，我们报告了一个全面的结构-活性关系的研究NK 3R-选择性激动剂肽，senktide。用草酰-Glu、草酰-D-Glu或草酰-L-2-氨基己二酸（Aad）取代senktide中的N-末端琥珀酰-Asp亚结构增加受体结合和NK 3R活化。在这些修饰中，草酰-D-Glu亚结构防止中性内肽酶（NEP）24.11介导的降解，从而提供了具有有利的生物学和稳定性性质的新型NK 3R激动剂肽。
Neurokinin B (NKB) regulates the secretion of gonadotropin-releasing hormone (GnRH) in the hypothalamus via activation of the cognate neurokinin-3 receptor (NK3R). The stimulatory effect of NKB and the derivatives on gonadotropin secretion can potentially be used for development of novel regulatory and therapeutic agents for reproductive dysfunctions. Here, we report a comprehensive structure–activity relationship study on the NK3R-selective agonist peptide, senktide. Substitution of the N-terminal succinyl-Asp substructure in senktide with oxalyl-Glu, oxalyl-D-Glu or oxalyl-L-2-aminoadipic acid (Aad) increased receptor binding and NK3R activation. Among these modifications, the oxalyl-D-Glu substructure prevented neutral endopeptidase (NEP) 24.11-mediated degradation, thus providing a novel NK3R agonist peptide with favourable biological and stability properties.