1-{[(4R,7S,10S,13S,16S)-7-(2-氨基-2-氧代乙基)-13-苄基-16-(4-羟基苄基)-10-异丁基-6,9,12,15,18-五氧代-1,2-二硫杂-5,8,11,14,17-五氮杂环二十烷-4-基]羰基}-L-脯氨酰-L-赖氨酰甘氨酰胺 | 42061-33-6

• 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
• 中文名称: 1-{[(4R,7S,10S,13S,16S)-7-(2-氨基-2-氧代乙基)-13-苄基-16-(4-羟基苄基)-10-异丁基-6,9,12,15,18-五氧代-1,2-二硫杂-5,8,11,14,17-五氮杂环二十烷-4-基]羰基}-L-脯氨酰-L-赖氨酰甘氨酰胺
• 英文名称: d[Leu⁴,Lys⁸]VP
• 英文别名: [deamino-Cys(1),Leu(4),Lys(8)]vasopressin；d[Leu4,Lys8]-VP；(2S)-N-[(2S)-6-amino-1-[(2-amino-2-oxoethyl)amino]-1-oxohexan-2-yl]-1-[(4R,7S,10S,13S,16S)-7-(2-amino-2-oxoethyl)-13-benzyl-16-[(4-hydroxyphenyl)methyl]-10-(2-methylpropyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carbonyl]pyrrolidine-2-carboxamide
• CAS: 42061-33-6
• 化学式: C₄₇H₆₇N₁₁O₁₁S₂
• 分子量: 1026.25
• InChiKey: QGZMLGLFLYCDQT-PEAOEFARSA-N

物化性质

• 沸点：
  1493.5±65.0 °C(Predicted)
• 密度：
  1.260±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.6
• 重原子数：
  71
• 可旋转键数：
  18
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  407
• 氢给体数：
  11
• 氢受体数：
  14

制备方法与用途

生物活性

D[LEU4,LYS8]-VP 是血管加压素 V1b 受体的选择性激动剂，对大鼠、人类和小鼠 V1b 受体的 Ki 值分别为 0.16 nM、0.52 nM 和 1.38 nM。D[LEU4,LYS8]-VP 具有较弱的抗利尿剂、升压药和体外催产素活性。

靶点

vasopressin V_1b receptor

反应信息

• 作为反应物：
  描述：

  1-{[(4R,7S,10S,13S,16S)-7-(2-氨基-2-氧代乙基)-13-苄基-16-(4-羟基苄基)-10-异丁基-6,9,12,15,18-五氧代-1,2-二硫杂-5,8,11,14,17-五氮杂环二十烷-4-基]羰基}-L-脯氨酰-L-赖氨酰甘氨酰胺 在 1-羟基苯并三唑 、 N,N'-二环己基碳二亚胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 生成 [deamino-Cys(1),Leu(4),Lys(β-Ala)(8)]vasopressin
  参考文献：
  名称：

  Design, Synthesis, and Pharmacological Characterization of Fluorescent Peptides for Imaging Human V1b Vasopressin or Oxytocin Receptors

  摘要：

  Among the four known vasopressin and oxytocin receptors, the specific localization of the V1b isoform is poorly described because of the lack of selective pharmacological tools. In an attempt to address this need, we decided to :design, synthesize, and characterize fluorescent selective V1b analogues. Starting. with tilt selective V1b agonist [deamino-Cys(1),Leu(4),Lys(8)]vasopressin (d[Leu(4), Lys(8)]VP) synthesized earlier, we added blue, green, or red fluorophores to the lysine residue at position 8 either directly:or by the use of linkers of different lengths. Among the nine analogues synthesized, two exhibited very promising properties. These are d[Leu(4),Lys(Alexa 647)(8)]VP (3) and d[Leu(4),Lys(11-aminoundecanoyl-Alexa 647)(8)]VP (9). They remained full V1b agonists with nanomolar affinity and specifically decorated the plasma membrane of CHO cells stably transfected with the human V1b receptor. These new selective fluorescent peptides will allow the cellular localization of V1b or OT receptor isoforms in native tissues.

  DOI：

  10.1021/jm1016208
• 作为产物：
  描述：

  (2-chlorophenyl)methyl N-[(5S)-5-[[(2S)-1-[(2R)-2-[[(2S)-4-amino-2-[[(2S)-4-methyl-2-[[(2S)-2-[[(2S)-2-[3-[(4-methylphenyl)methylsulfanyl]propanoylamino]-3-(4-phenylmethoxyphenyl)propanoyl]amino]-3-phenylpropanoyl]amino]pentanoyl]amino]-4-oxobutanoyl]amino]-3-benzylsulfanylpropanoyl]pyrrolidine-2-carbonyl]amino]-6-[(2-amino-2-oxoethyl)amino]-6-oxohexyl]carbamate 在 氨 、 sodium 、 ammonium hydroxide 、 溶剂黄146 、 potassium hexacyanoferrate(III) 作用下， 以59.9%的产率得到1-{[(4R,7S,10S,13S,16S)-7-(2-氨基-2-氧代乙基)-13-苄基-16-(4-羟基苄基)-10-异丁基-6,9,12,15,18-五氧代-1,2-二硫杂-5,8,11,14,17-五氮杂环二十烷-4-基]羰基}-L-脯氨酰-L-赖氨酰甘氨酰胺
  参考文献：
  名称：

  Design and Synthesis of the First Selective Agonists for the Rat Vasopressin V_1b Receptor:  Based on Modifications of Deamino-[Cys]arginine Vasopressin at Positions 4 and 8

  摘要：

  The neurohypophyseal peptides arginine vasopressin (AVP) and oxytocin (OT) mediate a wide variety of peripheral and central physiological and behavioral effects by acting on four different G-protein coupled receptors, termed V-1a (vascular), V-1b (pituitary), V-2 (renal), and OT (uterine). We recently reported that d[Cha(4)]AVP (A), d[Leu(4)]AVP (B), d[Orn(4)]AVP (C), and d[Arg(4)]AVP (D) have high affinity and are selective agonists for the human V-1b receptor. However, peptides A-D were subsequently shown to be potent antidiuretic agonists in the rat and are, thus, not selective V-1b agonists in the rat. Peptides A-D served as leads for the studies reported here. They were modified at position 8 by Lys, ornithine (Orn), diaminobutyric acid (Dab), and diaminopropionic acid (Dap) to give d[Cha(4),Lys(8)]VP (1), d[Cha(4),Orn(8)]VP (2), d[Cha(4),Dab(8)]VP (3), d[Cha(4),Dap(8)]VP (4), d[Leu(4),Lys(8)]VP (5), d[Leu(4),Orn(8)]VP (6), d[Leu(4),Dab(8)]VP (7), d[Leu(4),Dap(8)]VP (8), d[Orn(4),Lys(8)]VP (9), d[Orn(4),Orn(8)]VP (10), d[Arg(4),Lys(8)]VP (11), d[Arg(4),Orn(8)]VP (12), and d[Arg(4),Dab(8)]VP (13). All peptides were synthesized by the Merrifield solid-phase method. Their binding and functional properties were evaluated in rat AVP V-1a, V-1b, and V-2 receptors and on the rat OT receptor expressed either in native tissues or in stably transfected cells. They were also examined in rat vasopressor, antidiuretic, and in in vitro (no Mg++) oxytocic assays. Functional studies performed on chinese hamster ovary cells expressing the different AVP/OT receptors confirm that d[Cha(4),Lys(8)]VP (1), d[Cha(4),Dab(8)]VP (3), d[Leu(4),Lys(8)]VP (5), and d[Leu(4),Dap(8)]VP (8) are the first selective agonists for the rat V-1b receptor. These selective V-1b agonists are promising new tools for studies of the role of the V-1b receptor in the rat.

  DOI：

  10.1021/jm060928n

文献信息

• Design and Synthesis of the First Selective Agonists for the Rat Vasopressin V_1b Receptor:  Based on Modifications of Deamino-[Cys]arginine Vasopressin at Positions 4 and 8
  作者：Ana Pena、Brigitte Murat、Miguel Trueba、Maria A. Ventura、Nga C. Wo、Hazel H. Szeto、Ling Ling Cheng、Stoytcho Stoev、Gilles Guillon、Maurice Manning

  DOI：10.1021/jm060928n

  日期：2007.2.1

  The neurohypophyseal peptides arginine vasopressin (AVP) and oxytocin (OT) mediate a wide variety of peripheral and central physiological and behavioral effects by acting on four different G-protein coupled receptors, termed V-1a (vascular), V-1b (pituitary), V-2 (renal), and OT (uterine). We recently reported that d[Cha(4)]AVP (A), d[Leu(4)]AVP (B), d[Orn(4)]AVP (C), and d[Arg(4)]AVP (D) have high affinity and are selective agonists for the human V-1b receptor. However, peptides A-D were subsequently shown to be potent antidiuretic agonists in the rat and are, thus, not selective V-1b agonists in the rat. Peptides A-D served as leads for the studies reported here. They were modified at position 8 by Lys, ornithine (Orn), diaminobutyric acid (Dab), and diaminopropionic acid (Dap) to give d[Cha(4),Lys(8)]VP (1), d[Cha(4),Orn(8)]VP (2), d[Cha(4),Dab(8)]VP (3), d[Cha(4),Dap(8)]VP (4), d[Leu(4),Lys(8)]VP (5), d[Leu(4),Orn(8)]VP (6), d[Leu(4),Dab(8)]VP (7), d[Leu(4),Dap(8)]VP (8), d[Orn(4),Lys(8)]VP (9), d[Orn(4),Orn(8)]VP (10), d[Arg(4),Lys(8)]VP (11), d[Arg(4),Orn(8)]VP (12), and d[Arg(4),Dab(8)]VP (13). All peptides were synthesized by the Merrifield solid-phase method. Their binding and functional properties were evaluated in rat AVP V-1a, V-1b, and V-2 receptors and on the rat OT receptor expressed either in native tissues or in stably transfected cells. They were also examined in rat vasopressor, antidiuretic, and in in vitro (no Mg++) oxytocic assays. Functional studies performed on chinese hamster ovary cells expressing the different AVP/OT receptors confirm that d[Cha(4),Lys(8)]VP (1), d[Cha(4),Dab(8)]VP (3), d[Leu(4),Lys(8)]VP (5), and d[Leu(4),Dap(8)]VP (8) are the first selective agonists for the rat V-1b receptor. These selective V-1b agonists are promising new tools for studies of the role of the V-1b receptor in the rat.
• Design, Synthesis, and Pharmacological Characterization of Fluorescent Peptides for Imaging Human V1b Vasopressin or Oxytocin Receptors
  作者：Maithé Corbani、Miguel Trueba、Stoytcho Stoev、Brigitte Murat、Julie Mion、Véra Boulay、Gilles Guillon、Maurice Manning

  DOI：10.1021/jm1016208

  日期：2011.4.28

  Among the four known vasopressin and oxytocin receptors, the specific localization of the V1b isoform is poorly described because of the lack of selective pharmacological tools. In an attempt to address this need, we decided to :design, synthesize, and characterize fluorescent selective V1b analogues. Starting. with tilt selective V1b agonist [deamino-Cys(1),Leu(4),Lys(8)]vasopressin (d[Leu(4), Lys(8)]VP) synthesized earlier, we added blue, green, or red fluorophores to the lysine residue at position 8 either directly:or by the use of linkers of different lengths. Among the nine analogues synthesized, two exhibited very promising properties. These are d[Leu(4),Lys(Alexa 647)(8)]VP (3) and d[Leu(4),Lys(11-aminoundecanoyl-Alexa 647)(8)]VP (9). They remained full V1b agonists with nanomolar affinity and specifically decorated the plasma membrane of CHO cells stably transfected with the human V1b receptor. These new selective fluorescent peptides will allow the cellular localization of V1b or OT receptor isoforms in native tissues.