H-Cpa-cyclo-Nal-NH2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: H-Cpa-cyclo-Nal-NH2
• 英文别名: Cpa-cyclo(DCys-Pal-DTrp-Lys-Thr-Cys)-Nal-NH2；H-Phe(4-Cl)-D-Cys(1)-3Pal-D-Trp-Lys-Thr-Cys(1)-2Nal-NH2；(4R,7S,10S,13R,16S,19S)-10-(4-aminobutyl)-19-[[(2S)-2-amino-3-(4-chlorophenyl)propanoyl]amino]-N-[(2S)-1-amino-3-naphthalen-2-yl-1-oxopropan-2-yl]-7-[(1R)-1-hydroxyethyl]-13-(1H-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-16-(pyridin-3-ylmethyl)-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxamide
• 化学式: C₅₇H₆₇ClN₁₂O₉S₂
• 分子量: 1163.82
• InChiKey: PDOUJSYSARKFTN-DAQJOGRASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  81
• 可旋转键数：
  18
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  398
• 氢给体数：
  12
• 氢受体数：
  14

反应信息

• 作为产物：
  描述：

  H-Cpa-DCys-Pal-DTrp-Lys-Thr-Cys-Nal-NH2 在 碘 、 溶剂黄146 作用下， 反应 0.25h， 生成 H-Cpa-cyclo-Nal-NH2
  参考文献：
  名称：

  Highly Potent Cyclic Disulfide Antagonists of Somatostatin

  摘要：

  The search for synthetic analogues of somatostatin (SRIF) which exhibit selective affinities for the five known receptor subtypes (sst(1-5)) has generated a large number of potent agonist analogues. Many of these agonists display good subtype selectivities and affinities for the subtypes 2, 3, and 5, with very few selective for sst(1) or sst(4). Until the recent report by Bass and co-workers (Mol. Pharmacol. 1996, 50, 709-715; erratum Mel. Pharmacol. 1997, 51, 170), no true antagonists of somatostatin had been discovered, let alone any displaying differential receptor subtype selectivity. In this present study, we further explore the effect of this putative L,D-5(6) antagonist motif on somatostatin octapeptide analogues with a cyclic hexapeptide core. The most potent antagonist found to date is H-Cpa-cyclo[DCys-Tyr-DTrp-Lys-Thr-Cys]-Nal-NH2, PRL-2970 (21), which has an IC50 Of 1.1 nM in a rat pituitary growth hormone in vitro antagonist assay versus SRIF (1 nM). This analogue bound to cloned human somatostatin subtype 2 receptors with a K-i of 26 nM. The highest hsst(2) affinity analogue was H-Cpa-cyclo[DCys-Pal-DTrp-Lys-Tle-Cys]-Nal-NH2, PRL-2915 (15), with a K-i of 12 nM (IC50 = 1.8 nM). This analogue was also selective for hsst(2) over hsst(3) and hsst(5) by factors of 8 and 40, respectively, and had no agonist activity when tested alone at concentrations up to 10 mu M. Regression analysis of the binding affinities versus the observed antagonist potencies revealed high correlations for hsst(2) (r = 0.65) and hsst(3) (r = 0.52) with a less significant correlation to hsst5 (r = 0.40). This is quite different from the somatostatin agonist analogues which show a highly significant correlation to hsst(2) (r > 0.9). Receptor-selective somatostatin antagonists should provide valuable tools for characterizing the many important physiological functions of this neuropeptide.

  DOI：

  10.1021/jm9806289

文献信息

• Highly Potent and Subtype Selective Ligands Derived by <i>N</i>-Methyl Scan of a Somatostatin Antagonist
  作者：W. G. Rajeswaran、Simon J. Hocart、William A. Murphy、John E. Taylor、David H. Coy

  DOI：10.1021/jm0005048

  日期：2001.4.1

  The search for synthetic peptide analogues of somatostatin (SRIF) which exhibit selective affinities for the five known receptor subtypes (sst1-5) has generated a large number of potent agonists. Some of these agonists display good subtype selectivities and affinities for the subtypes 1, 2, 3, and 5, including analogues created by N-methyl amino acid substitutions in a standard octapeptide analogue

  寻找对五种已知受体亚型（sst1-5）具有选择性亲和力的生长抑素的合成肽类似物（SRIF）已产生了大量有效的激动剂。这些激动剂中的一些对亚型1、2、3和5表现出良好的亚型选择性和亲和力，包括由标准八肽类似物形式的N-甲基氨基酸取代产生的类似物。现在，我们已使用该实验室报告的拮抗剂Cpa-环（DCys-Pal-DTrp-Lys-Thr-Cys）-Nal-NH2 9作为前导结构，将该肽骨架N-甲基化方法扩展为有效的生长抑素受体拮抗剂系列。 。测试了合成类似物抑制生长抑素刺激的培养物中大鼠垂体细胞释放GH的能力，以及从用五种已知人类生长抑素受体转染的CHO细胞中置换125 I标记的生长抑素的能力。这项研究得出了一些有趣的发现。在Lys（9）残基（5）处的N-甲基化使大鼠GH释放抑制能力增加了近4倍，达到0.73 nM，但对人2型受体的结合亲和力几乎没有变化。该类似物还对sst5受体具有5.98 nM的高亲和力（相对于生长抑素本身为1