Structure-activity relationship study and NMR analysis of fluorobenzoyl pentapeptide GPR54 agonists
Structure-activity relationship study and NMR analysis of fluorobenzoyl pentapeptide GPR54 agonists
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DOI：
10.1002/bip.20968
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发表时间：
2008-01-01
期刊：
影响因子：
2.9
通讯作者：
Fujii, Nobutaka
中科院分区：
文献类型：
--
作者：
Tomita, Kenji;Oishi, Shinya;Fujii, Nobutaka
GPR54是一种GQ蛋白偶联受体，参与肿瘤转移和内分泌系统的调节。内源性配体激活GPR54可减弱肿瘤的流动性，刺激促性腺激素释放激素的分泌。因此，Gpr54激动剂是治疗癌症转移和激素疾病的潜在候选药物。在我们以前的研究中，Kispeptin C末端的五肽衍生物被鉴定为有效的GPR54激动剂。在本研究中，我们研究了N-末端具有不同氟取代苯甲酰基的五肽的构效关系。其中，4-氟苯甲酰衍生物是最有效的激动剂。另一方面，具有多个氟取代基的衍生物的结合亲和力较小。这些多肽及其N端部分结构的核磁共振分析表明，氟取代基影响苯甲酰基的构象。由于邻氟和酰胺氢之间的分子内Cf-HN氢键，O-单氟苯甲酰基可能是以共面构象存在的；o，o-二氟苯甲酰基部分可能由于两个邻氟原子与羰基氧之间的空间位阻和/或静电斥力而以扭曲的构象存在。(C)2008年威利期刊公司。
GPR54 is a Gq-protein coupled receptor involved in cancer metastasis and regulation of the endocrine system. GPR54 activation by endogenous ligands attenuates the mobility of carcinomas and stimulates the secretion of gonadotropin-releasing hormone. GPR54 agonists are, therefore, potential therapeutic candidates for cancer metastasis and hormonal diseases. Pentapeptide derivatives of kisspeptin C-terminus were identified as potent GPR54 agonists in our previous studies. In the present study, we investigated the structure-activity relationship of a variety of pentapeptides having various fluorine-substituted benzoyl groups at the N-terminus. Among these, a 4-fluorobenzoyl derivative was the most potent agonist. On the other hand, the derivatives having multiple fluoro-substituting groups showed less binding affinity. NMR analysis of these peptides and their N-terminal partial structures suggested that fluorine substituents affect the benzoyl conformation. o-Monofluorobenzoyl is likely to be in a coplanar conformation due to the intramolecular CF-HN hydrogen bonding between o-fluorine and amide hydrogen; the o,o-difluorobenzoyl moiety exists in a distorted conformation probably due to the steric hindrance and/or electrostatic repulsion between two o-fluorine atoms and carbonyl oxygen. (C) 2008 Wiley Periodicals, Inc.