Boc-Trp-Chg-Asp-1Nal-N(CH3)2

• 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: Boc-Trp-Chg-Asp-1Nal-N(CH3)2
• 英文别名: Boc-Trp-Chg-Asp-1Nal-NMe2；(3S)-3-[[(2S)-2-cyclohexyl-2-[[(2S)-3-(1H-indol-3-yl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]amino]acetyl]amino]-4-[[(2S)-1-(dimethylamino)-3-naphthalen-1-yl-1-oxopropan-2-yl]amino]-4-oxobutanoic acid
• 化学式: C₄₃H₅₄N₆O₈
• 分子量: 782.937
• InChiKey: QQOBHBRESGSVEE-SZHYKVQFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.8
• 重原子数：
  57
• 可旋转键数：
  17
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  199
• 氢给体数：
  6
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  N-叔丁氧羰基-L-色氨酸 在 palladium on activated charcoal 氢气 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 10.0h， 生成 Boc-Trp-Chg-Asp-1Nal-N(CH3)2
  参考文献：
  名称：

  CCK-B agonist or antagonist activities of structurally hindered and peptidase-resistant Boc-CCK4 derivatives

  摘要：

  Replacement of Met31 by (N-Me)Nle in CCK8 or CCK4 has been shown to improve the affinity and selectivity for CCK-B receptors. In order to obtain molecules with enhanced bioavailability, two novel series of protected tetrapeptides of the general formula Boc-Trp30-X-Asp-Y33 have been developed. Introduction of (N-Me)Nle and the bulky, aromatic naphthylalaninamide (Nal-NH2) in positions X and Y, respectively, does not greatly modify the affinity for guinea pig brain CCK-B receptors. In contrast, incorporation of hindering N-methyl amino acids such as (N-Me)Phe, (N-Me)Phg, or (N-Me)Chg, but not their non-methylated counterparts, in position X induced a large decrease in affinity for the CCK-B binding sites. Among the various peptides synthesized, Boc-[(N-Me)Nle31,1Nal-NH233]CCK4 (2) (K(I) = 2.8 nM), Boc-[Phg31,1Nal-NH233]CCK4 (15) (K(I) = 14 nM), and Boc-[Phg31,1Nal-N(CH3)233]CCK4 (17) (K(I) = 39 nM) displayed good affinities for brain CCK-B receptors and had good selectivity ratios. These pseudopeptides, in which the presence of unnatural and hydrophobic residues is expected to improve their penetration of the central nervous system, were shown to be very resistant to brain peptidases. Interestingly, whereas compounds 2 and 15 proved to be full agonists for rat hippocampal CCK-B receptors when measured in an electrophysiological assay, compound 17 behaved as a potent antagonist in the same test and displayed a good affinity in rat brain K(I)(CCK-B) = 51 nM as compared to the Merck antagonist L365,260, K(I)(CCK-B) = 12 nM. This illustrates a simple means to obtain CCK-B antagonists and suggests that the free, CONH2 group plays a critical role in the recognition of the agonist date of brain CCK-B receptors.

  DOI：

  10.1021/jm00053a022

文献信息

• CCK-B agonist or antagonist activities of structurally hindered and peptidase-resistant Boc-CCK4 derivatives
  作者：P. J. Corringer、J. H. Weng、B. Ducos、C. Durieux、P. Boudeau、A. Bohme、B. P. Roques

  DOI：10.1021/jm00053a022

  日期：1993.1

  Replacement of Met31 by (N-Me)Nle in CCK8 or CCK4 has been shown to improve the affinity and selectivity for CCK-B receptors. In order to obtain molecules with enhanced bioavailability, two novel series of protected tetrapeptides of the general formula Boc-Trp30-X-Asp-Y33 have been developed. Introduction of (N-Me)Nle and the bulky, aromatic naphthylalaninamide (Nal-NH2) in positions X and Y, respectively, does not greatly modify the affinity for guinea pig brain CCK-B receptors. In contrast, incorporation of hindering N-methyl amino acids such as (N-Me)Phe, (N-Me)Phg, or (N-Me)Chg, but not their non-methylated counterparts, in position X induced a large decrease in affinity for the CCK-B binding sites. Among the various peptides synthesized, Boc-[(N-Me)Nle31,1Nal-NH233]CCK4 (2) (K(I) = 2.8 nM), Boc-[Phg31,1Nal-NH233]CCK4 (15) (K(I) = 14 nM), and Boc-[Phg31,1Nal-N(CH3)233]CCK4 (17) (K(I) = 39 nM) displayed good affinities for brain CCK-B receptors and had good selectivity ratios. These pseudopeptides, in which the presence of unnatural and hydrophobic residues is expected to improve their penetration of the central nervous system, were shown to be very resistant to brain peptidases. Interestingly, whereas compounds 2 and 15 proved to be full agonists for rat hippocampal CCK-B receptors when measured in an electrophysiological assay, compound 17 behaved as a potent antagonist in the same test and displayed a good affinity in rat brain K(I)(CCK-B) = 51 nM as compared to the Merck antagonist L365,260, K(I)(CCK-B) = 12 nM. This illustrates a simple means to obtain CCK-B antagonists and suggests that the free, CONH2 group plays a critical role in the recognition of the agonist date of brain CCK-B receptors.