Analogues of growth hormone-releasing factor (1-29) amide containing the reduced peptide bond isostere in the N-terminal region.
Analogues of growth hormone-releasing factor (1-29) amide containing the reduced peptide bond isostere in the N-terminal region.
复制标题
生长激素释放因子 (1-29) 酰胺的类似物，在 N 末端区域含有还原的肽键等排体。
DOI：
10.1021/jm00169a022
复制
发表时间：
1990
影响因子：
7.3
通讯作者：
Coy,DH
中科院分区：
文献类型：
--
作者：
Hocart,SJ;Murphy,WA;Coy,DH
先前使用N [CH 2NH]肽键电子等排体的肽结构-活性研究在插入各种序列中时产生拮抗剂。这些包括蛙皮素，其中Leu 1V '[CH 2NH] Leu 14的掺入产生了一种有效的拮抗剂，和tetragastrin，其中Boc-Trp-Leu^[CH 2NH] Asp-Phe-NH 2是一种拮抗剂。在本研究中，我们选择研究这种电子等排体对生长激素释放因子（1-29）酰胺的影响。类似物通过固相合成制备，电子等排体通过在NaBH 3CN存在下与预先形成的保护的氨基酸醛进行无外消旋的还原烷基化来并入。在0 ℃下用LiAlH_4还原保护的A，O-二甲基异羟肟酸酯制备醛。纯化的类似物在4天的雄性大鼠垂体前叶细胞的生长激素（GH）释放的原代培养进行了测定。在存在GRF（1-29）NH 2的情况下重新测试潜在拮抗剂。在5-6位，产生了一种非常弱的激动剂，活性<0.01%。在位置1-2、2-3和6-7处并入电子等排体得到具有约0.1%活性的弱激动剂。分别在10-11和3-4掺入产生具有0.39%和1.6%活性的激动剂。发现类似物[Ser 91//[CH 2NH] Tyr 10] GRF（1 -29）NH 2在10 μ M时是拮抗剂。生长激素释放因子（GRF）是一种44-残基肽，从肢端肥大症患者的胰腺肿瘤中分离得到。2，3 GRF的结构特征导致了大量的基础和临床研究，以了解该肽在控制GH分泌中的作用及其对生长本身的最终影响。结构-活性研究表明，活性不需要完整的序列，缩短的序列GRF（I-29）NH 2是完全有效的，3大大简化了类似物的合成，用于进一步的结构-活性研究。迄今积累的数据表明，GRF可能在某些疾病，包括儿童GH缺乏症，以及在有关牛奶和肉类生产的农业应用的价值。与许多其他肽类激素一样，GRF的血浆半衰期为几分钟。4这是开发有效的长效治疗剂或农用制剂的一个主要问题。增加类似物的效力和作用持续时间的最常见方法是在激素的各个区域掺入不寻常的或D-氨基酸残基。5*”9
Previous peptide structure-activity investigations employing the i/'[CH2NH] peptide bond isostere have produced antagonists when inserted into various sequences. Theseinclude bombesin, in which the incorporation of Leu1V'[CH2NH] Leu14 produced a potent antagonist, and tetragastrin, with which Boc-Trp-Leu^[CH2NH] Asp-Phe-NH2 is an antagonist. In thisstudy, we chose to investigate the effect of this isostere on growth hormone-releasing factor (1-29) amide. Analogues were prepared by solid-phase synthesis and the isosteres incorporated by racemization-free reductive alkylationwith a preformed protected amino acid aldehyde in the presence of NaBH3CN. The aldehydes were prepared by the reduction of the protected A, O-dimethyl hydroxamates with LiAlH4 at 0 C. The purified analogues were assayed in a 4-day primary culture of male rat anterior pituitary cells for growth hormone (GH) release. Potential antagonists were retested in the presence of GRF (1-29) NH2. The followingresults were obtained: At position 5-6, a very weak agonist was produced with «0.01% activity. Incorporation of the isostere in positions 1-2, 2-3, and 6-7 gave weak agonists with~ 0.1% activity. Agonists with 0.39% and 1.6% activity were produced by incorporation at 10-11 and 3-4, respectively. The analogue [Ser9i//[CH2NH] Tyr10] GRF (l-29) NH2 was found to be an antagonist in the 10 tiM. range vs 1 nM GRF and had no agonist activity at doses as high as 0.1 mM.Growth hormone-releasing factor (GRF), a 44-residue peptide, was isolated from a pancreatic tumor occurring in an acromegalic patient. 2, 3 The structural characteri-zation of GRF has resulted in numerous basic and clinical studies into this peptide’srole in the control of GH se-cretion and its ultimate effects on growth itself. Struc-ture-activity studies have shown that the full sequence is not required for activity and that the shortened sequence GRF (I-29) NH2 is fully potent, 3 greatly simplifying the synthesis of analogues for further structure-activity studies. The data accumulated thus far indicate that GRF may be of value in certainclinical disorders, including childhood GH deficiency, as well as in agricultural ap-plications pertaining to milk and meat production. In common with a number of other peptide hormones, the plasma half-life of GRF is of the order of minutes. 4 This presents a major problem in the development of potent long-acting therapeutic or agricultural agents. The most common approach to increasing the potency and duration of action of analogues has been the incorporation of unu-sual or D-amino acid residues in various regions of the hormone. 5*" 9