Arg-Arg-Pro-Tyr-N^α-methyl-Ile-Leu | 1092172-26-3

• 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: Arg-Arg-Pro-Tyr-N^α-methyl-Ile-Leu
• 英文别名: H-Arg-Arg-Pro-Tyr-N-Me-Ile-Leu-OH；[N-Me-Ile(12)]NT(8-13)；(2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]-3-(4-hydroxyphenyl)propanoyl]-methylamino]-3-methylpentanoyl]amino]-4-methylpentanoic acid
• CAS: 1092172-26-3
• 化学式: C₃₉H₆₆N₁₂O₈
• 分子量: 831.029
• InChiKey: AGCKRBKIEACUSP-VGPFALITSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -2.3
• 重原子数：
  59
• 可旋转键数：
  24
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  340
• 氢给体数：
  10
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  Arg-Arg-Pro-Tyr-N^α-methyl-Ile-Leu 、 三氟乙酸 以 水 为溶剂， 反应 3.0h， 以6.7 mg的产率得到Arg-Arg-Pro-Tyr-N^α-methyl-Ile-Leu tris(hydrotrifluoroacetate)
  参考文献：
  名称：

  在Arg和Ile处的修饰使Neurotensin（8-13）衍生物具有高稳定性并保留了NTS1受体亲和力。

  摘要：

  由于其在各种恶性肿瘤中的表达，已经提出并探索了神经降压素受体1（NTS 1 R）作为肿瘤诊断和治疗的靶标。基于动物模型的对六肽神经降压素（8-13）（NT（8-13））衍生的各种放射性标记的NTS 1 R配体的研究，例如用于PET诊断的68 Ga和18 F标记的化合物，可以优化用于临床的放射性示踪剂。由于NT（8-13）在体内迅速降解；就增加的代谢稳定性而言，需要进行结构修饰。在这项研究中，通过进行N-甲基扫描（取代Ile ）系统性地探索了NT（8-13）肽骨架对酶促降解的稳定性。12由叔-butylglycine 12（TLE 12）和N-末端酰化。精氨酸，Arg 8或Arg 9的N-甲基化结合Ile 12 / Tle 12交换被证明对NTS 1 R亲和力（K i <2 nM）和在人血浆中的稳定性最有利（t 1/2 > 48 h），这是开发源自NT（8-13）的放射性药物的宝贵结果。

  DOI：

  10.1021/acsmedchemlett.9b00122
• 作为产物：
  描述：

  6-(4-Methoxy-3-(oxazol-5-yl)phenyl)-4-methylhex-4-enoic acid 在 三异丙基硅烷 、 水 、 三氟乙酸 、 苯酚 作用下， 反应 2.0h， 生成 Arg-Arg-Pro-Tyr-N^α-methyl-Ile-Leu
  参考文献：
  名称：

  Novel insights into GPCR—Peptide interactions: Mutations in extracellular loop 1, ligand backbone methylations and molecular modeling of neurotensin receptor 1

  摘要：

  Investigating prototypical interactions between NT(8-13) and the human neurotensin receptor 1 (hNTR1), we created a receptor-ligand model that was validated by site-directed mutagenesis and structure-activity relationship studies. Stabilization of the extracellular loop 1 (EL1) by pi-stacking clusters proved to be important for agonist binding when substitution of six conserved amino acids by alanine resulted in an agonist specific loss of maximal binding capacity. In agreement with our modeling studies, EL1 seems to adopt a clamp-type border area controlling the shape of the binding site crevice. Employing chemically manipulated peptide analogs as molecular probes, the impact of backbone modi. cations on receptor-ligand interaction, especially the influence on ligand conformation, was examined in binding studies and explained by in silico analysis. (c) 2008 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2008.08.051

文献信息

• Novel insights into GPCR—Peptide interactions: Mutations in extracellular loop 1, ligand backbone methylations and molecular modeling of neurotensin receptor 1
  作者：Steffen Härterich、Susanne Koschatzky、Jürgen Einsiedel、Peter Gmeiner

  DOI：10.1016/j.bmc.2008.08.051

  日期：2008.10

  Investigating prototypical interactions between NT(8-13) and the human neurotensin receptor 1 (hNTR1), we created a receptor-ligand model that was validated by site-directed mutagenesis and structure-activity relationship studies. Stabilization of the extracellular loop 1 (EL1) by pi-stacking clusters proved to be important for agonist binding when substitution of six conserved amino acids by alanine resulted in an agonist specific loss of maximal binding capacity. In agreement with our modeling studies, EL1 seems to adopt a clamp-type border area controlling the shape of the binding site crevice. Employing chemically manipulated peptide analogs as molecular probes, the impact of backbone modi. cations on receptor-ligand interaction, especially the influence on ligand conformation, was examined in binding studies and explained by in silico analysis. (c) 2008 Elsevier Ltd. All rights reserved.
• Modifications at Arg and Ile Give Neurotensin(8–13) Derivatives with High Stability and Retained NTS₁ Receptor Affinity
  作者：Lisa Schindler、Günther Bernhardt、Max Keller

  DOI：10.1021/acsmedchemlett.9b00122

  日期：2019.6.13

  Due to its expression in various malignant tumors, the neurotensin receptor 1 (NTS1R) has been suggested and explored as a target for tumor diagnosis and therapy. Animal model-based investigations of various radiolabeled NTS1R ligands derived from the hexapeptide neurotensin(8–13) (NT(8–13)), e.g. 68Ga- and 18F-labeled compounds for PET diagnostics, give rise to optimize such radiotracers for clinical

  由于其在各种恶性肿瘤中的表达，已经提出并探索了神经降压素受体1（NTS 1 R）作为肿瘤诊断和治疗的靶标。基于动物模型的对六肽神经降压素（8-13）（NT（8-13））衍生的各种放射性标记的NTS 1 R配体的研究，例如用于PET诊断的68 Ga和18 F标记的化合物，可以优化用于临床的放射性示踪剂。由于NT（8-13）在体内迅速降解；就增加的代谢稳定性而言，需要进行结构修饰。在这项研究中，通过进行N-甲基扫描（取代Ile ）系统性地探索了NT（8-13）肽骨架对酶促降解的稳定性。12由叔-butylglycine 12（TLE 12）和N-末端酰化。精氨酸，Arg 8或Arg 9的N-甲基化结合Ile 12 / Tle 12交换被证明对NTS 1 R亲和力（K i <2 nM）和在人血浆中的稳定性最有利（t 1/2 > 48 h），这是开发源自NT（8-13）的放射性药物的宝贵结果。