[Mpa(H)¹,Cys(H)⁶]oxytocin

• 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: [Mpa(H)¹,Cys(H)⁶]oxytocin
• 英文别名: deamino-Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH2；(2S)-N-[(2S)-4-amino-1-[[(2R)-1-[(2S)-2-[[(2S)-1-[(2-amino-2-oxoethyl)amino]-4-methyl-1-oxopentan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxo-3-sulfanylpropan-2-yl]amino]-1,4-dioxobutan-2-yl]-2-[[(2S,3S)-2-[[(2S)-3-(4-hydroxyphenyl)-2-(3-sulfanylpropanoylamino)propanoyl]amino]-3-methylpentanoyl]amino]pentanediamide
• 化学式: C₄₃H₆₇N₁₁O₁₂S₂
• 分子量: 994.203
• InChiKey: FOUPISJGJLIPAA-QPLNMOKZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.6
• 重原子数：
  68
• 可旋转键数：
  29
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  376
• 氢给体数：
  13
• 氢受体数：
  14

反应信息

• 作为反应物：
  描述：

  [Mpa(H)¹,Cys(H)⁶]oxytocin 在 氧气 作用下， 以 aq. buffer 为溶剂， 反应 72.0h， 以17%的产率得到deamino-oxytocin
  参考文献：
  名称：

  建立高选择性，有效和稳定的催产素和加压素类似物的桥梁

  摘要：

  催产素（OT）是一种令人兴奋的潜在治疗剂，但它对修饰高度敏感，并在高温和体内遭受广泛降解。在这里，我们报告了对OT类似物的研究，该研究对催产素受体（OTR）具有良好的选择性，亲和力和效力，此外还通过用取代的二溴二甲苯类似物桥接二硫键区域来提高肽的稳定性。我们发现在其中间环化类似物（DOT敏感结构-活性关系的元），得到最高的亲和力（50nM的ķ我），选择性（34倍），和激动剂效力（34 nM的EC 50，87倍的选择性）朝向OTR。出人意料的是，邻环化的类似物证明了OTR和加压素V 1a受体亚型亲和力（分别为220 nM和69 nM）和药理活性（分别为294 nM和35 nM）。通过用碱性氨基酸取代位置8处的中性残基，可以提高对邻环化肽的V 1a结合力和选择性6倍，从而提供不显示OTR活化作用的强效拮抗剂（14 nM IC 50）。此外，在高温下，与OT相比，二甲苯桥接的类似物表现出更高的稳

  DOI：

  10.1016/j.bmc.2018.03.019
• 作为产物：
  描述：

  3-(三苯甲硫基)丙酸 、 Fmoc-L-异亮氨酸 、 Fmoc-O-叔丁基-L-酪氨酸 、 Fmoc-S-三苯甲基-L-半胱氨酸 、 alkaline earth salt of/the/ methylsulfuric acid 生成 [Mpa(H)¹,Cys(H)⁶]oxytocin
  参考文献：
  名称：

  A Study of the Relationship between Biological Activity and Prolyl Amide Isomer Geometry in Oxytocin Using 5-tert-Butylproline To Augment the Cys⁶-Pro⁷ Amide Cis-Isomer Population

  摘要：

  Three [5-t-BuPro(7)]oxytocin analogues were synthesized by substituting (2S,5R)-5-tert-butyl-proline for proline in oxytocin, [Mpa(1)]oxytocin, and [dPen(1)]oxytocin. Relative to oxytocin, [5-t-BuPro(7)]oxytocin and [Mpa(1),5-t-BuPro(7)]oxytocin exhibited strongly reduced binding affinity to the receptor; however, both peptides maintained the pharmacophore characteristics responsible for signal transfer evoking the same maximal response as oxytocin in the single-dose procedure and exhibiting partial agonistic activity in the cumulative dose-response procedure. Although [dPen(1)]oxytocin exhibited inhibitory as well as partial agonistic activity, [dPen(1),5-t-BuPro(7)]oxytocin exhibited only inhibitory potency with a similar in vitro pA(2) value of 7.50 in the absence of magnesium. In the presence of magnesium, [dPen(1),5-t-BuPro7]oxytocin exhibited stronger inhibitory potency than [dPen(1)]oxytocin and no partial agonism. Assignment of the proton signals for the 5-tert-butylprolyl amide cis- and trans-isomers by two-dimensional NMR experiments in water indicated that the Cys(6)-Pro(7) peptide bond cis-isomer population was augmented relative to the prolyl peptides and measured respectively at 35%, 33%, and 20% in the 5-tert-butylproline(7) analogues of oxytocin, [Mpa(1)]oxytocin and [dPen(1)]oxytocin. Although caution must be taken when relating the increase in cis-isomer population with an influence on biological activity in [5-t-BuPro7(])oxytocin analogues, the synthesis and evaluation of analogues 1-3 have provided additional evidence that can be used to support the hypothesis that the prolyl amide cis-isomer may favor antagonism and the trans-isomer is necessary for agonist activity.

  DOI：

  10.1021/jm990090m

文献信息

• A Study of the Relationship between Biological Activity and Prolyl Amide Isomer Geometry in Oxytocin Using 5-<i>tert</i>-Butylproline To Augment the Cys⁶-Pro⁷ Amide <i>Cis</i>-Isomer Population
  作者：Laurent Bélec、Jirina Slaninova、William D. Lubell

  DOI：10.1021/jm990090m

  日期：2000.4.1

  Three [5-t-BuPro(7)]oxytocin analogues were synthesized by substituting (2S,5R)-5-tert-butyl-proline for proline in oxytocin, [Mpa(1)]oxytocin, and [dPen(1)]oxytocin. Relative to oxytocin, [5-t-BuPro(7)]oxytocin and [Mpa(1),5-t-BuPro(7)]oxytocin exhibited strongly reduced binding affinity to the receptor; however, both peptides maintained the pharmacophore characteristics responsible for signal transfer evoking the same maximal response as oxytocin in the single-dose procedure and exhibiting partial agonistic activity in the cumulative dose-response procedure. Although [dPen(1)]oxytocin exhibited inhibitory as well as partial agonistic activity, [dPen(1),5-t-BuPro(7)]oxytocin exhibited only inhibitory potency with a similar in vitro pA(2) value of 7.50 in the absence of magnesium. In the presence of magnesium, [dPen(1),5-t-BuPro7]oxytocin exhibited stronger inhibitory potency than [dPen(1)]oxytocin and no partial agonism. Assignment of the proton signals for the 5-tert-butylprolyl amide cis- and trans-isomers by two-dimensional NMR experiments in water indicated that the Cys(6)-Pro(7) peptide bond cis-isomer population was augmented relative to the prolyl peptides and measured respectively at 35%, 33%, and 20% in the 5-tert-butylproline(7) analogues of oxytocin, [Mpa(1)]oxytocin and [dPen(1)]oxytocin. Although caution must be taken when relating the increase in cis-isomer population with an influence on biological activity in [5-t-BuPro7(])oxytocin analogues, the synthesis and evaluation of analogues 1-3 have provided additional evidence that can be used to support the hypothesis that the prolyl amide cis-isomer may favor antagonism and the trans-isomer is necessary for agonist activity.
• Building bridges for highly selective, potent and stable oxytocin and vasopressin analogs
  作者：Rhiannon Beard、Andy Stucki、Muriel Schmitt、Gabrielle Py、Christophe Grundschober、Antony D. Gee、Edward W. Tate

  DOI：10.1016/j.bmc.2018.03.019

  日期：2018.7

  agent, but it is highly sensitive to modification and suffers extensive degradation at elevated temperature and in vivo. Here we report studies towards OT analogs with favorable selectivity, affinity and potency towards the oxytocin receptor (OTR), in addition to improving stability of the peptide by bridging the disulfide region with substituted dibromo-xylene analogs. We found a sensitive structure-activity

  催产素（OT）是一种令人兴奋的潜在治疗剂，但它对修饰高度敏感，并在高温和体内遭受广泛降解。在这里，我们报告了对OT类似物的研究，该研究对催产素受体（OTR）具有良好的选择性，亲和力和效力，此外还通过用取代的二溴二甲苯类似物桥接二硫键区域来提高肽的稳定性。我们发现在其中间环化类似物（DOT敏感结构-活性关系的元），得到最高的亲和力（50nM的ķ我），选择性（34倍），和激动剂效力（34 nM的EC 50，87倍的选择性）朝向OTR。出人意料的是，邻环化的类似物证明了OTR和加压素V 1a受体亚型亲和力（分别为220 nM和69 nM）和药理活性（分别为294 nM和35 nM）。通过用碱性氨基酸取代位置8处的中性残基，可以提高对邻环化肽的V 1a结合力和选择性6倍，从而提供不显示OTR活化作用的强效拮抗剂（14 nM IC 50）。此外，在高温下，与OT相比，二甲苯桥接的类似物表现出更高的稳