• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Journal of Molecular Biochemistry >Probing the GnRH receptor agonist binding site identifies methylated triptorelin as a new anti-proliferative agent
【24h】

Probing the GnRH receptor agonist binding site identifies methylated triptorelin as a new anti-proliferative agent

机译：探索GnRH受体激动剂结合位点可确定甲基化曲普瑞林是一种新的抗增殖药

获取原文
       
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

D-amino acid substitutions at Glycine postion-6 in GnRH-I decapeptide can possess super-agonist activity and enhanced in vivo pharmacokinetics. Agonists elicit growth-inhibition in tumorigenic cells expressing the GnRH receptor above threshold levels. However, new agonists with modified properties are required to improve the anti-proliferative range. Effects of residue substitutions and methylations on tumourigenic HEK293[SCL60] and WPE-1-NB26-3 prostate cells expressing the rat GnRH receptor were compared. Peptides were ranked according to receptor binding affinity, induction of inositol phosphate production and cell growth-inhibition. Analogues possessing D-Trp6 (including Triptorelin), D-Leu6 (including Leuprolide), D-Ala6, D-Lys6, or D-Arg6 exhibited agonist and anti-proliferative activity. Residues His5 or His5,Trp7,Tyr8, corresponding to residues found in GnRH-II , were tolerated, with retention of sub-nanomolar/low nanomolar binding affinities and EC50s for receptor activation and IC50s for cell growth-inhibition. His5D-Arg6-GnRH-I exhibited reduced binding affinity and potency, effective in the mid-nanomolar range. However, all GnRH-II-like analogues were less potent than Triptorelin. By comparison, three methylated-Trp6 Triptorelin variants showed differential binding, receptor activation and anti-proliferation potency. Significantly, 5-Methyl-DL-Trp6-Triptorelin was equipotent to triptorelin. Subsequent studies should determine whether pharmacologically enhanced derivatives of Triptorelin can be developed by further alkylations, without substitutions or cleavable cytotoxic adducts, to improve the extent of growth-inhibition of tumour cells expressing the GnRH receptor.
机译：GnRH-1十肽中甘氨酸6位的D-氨基酸取代可具有超激动剂活性并增强体内药代动力学。激动剂在表达高于阈值水平的GnRH受体的致瘤细胞中引起生长抑制。然而，需要具有修饰性质的新激动剂来改善抗增殖范围。比较了残基取代和甲基化对表达大鼠GnRH受体的致瘤性HEK293 [SCL60]和WPE-1-NB26-3前列腺细胞的影响。根据受体结合亲和力，磷酸肌醇生成的诱导和细胞生长的抑制对肽进行排名。具有D-Trp6（包括曲普瑞林），D-Leu6（包括亮丙瑞林），D-Ala6，D-Lys6或D-Arg6的类似物表现出激动剂和抗增殖活性。耐受对应于GnRH-II中发现的残基的His5或His5，Trp7，Tyr8，保留亚纳摩尔/低纳摩尔结合亲和力，EC50用于受体激活，IC50用于细胞生长抑制。 His5D-Arg6-GnRH-1表现出降低的结合亲和力和效力，在中纳摩尔范围内有效。但是，所有类似GnRH-II的类似物均不如曲普瑞林那么有效。相比之下，三种甲基化的Trp6 Triptorelin变体显示出不同的结合，受体激活和抗增殖能力。显着地，5-甲基-DL-Trp6-Triptorelin与曲普瑞林等效。随后的研究应确定曲普瑞林的药理学增强衍生物是否可以通过进一步的烷基化而不被取代或可裂解的细胞毒性加合物来开发，以改善表达GnRH受体的肿瘤细胞的生长抑制程度。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号