N-((S)-1-{3-[2-(2-Amino-acetylamino)-acetylamino]-phenyl}-2-pyrrolidin-1-yl-ethyl)-2-(3,4-dichloro-phenyl)-N-methyl-acetamide | 778641-25-1

• 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: N-((S)-1-{3-[2-(2-Amino-acetylamino)-acetylamino]-phenyl}-2-pyrrolidin-1-yl-ethyl)-2-(3,4-dichloro-phenyl)-N-methyl-acetamide
• 英文别名: N-[(1S)-1-[3-[[2-[(2-aminoacetyl)amino]acetyl]amino]phenyl]-2-pyrrolidin-1-ylethyl]-2-(3,4-dichlorophenyl)-N-methylacetamide
• CAS: 778641-25-1
• 化学式: C₂₅H₃₁Cl₂N₅O₃
• 分子量: 520.459
• InChiKey: ZEABJVOGZAUGSN-JOCHJYFZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  35
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  108
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  、 N-((S)-1-{3-[2-(2-Amino-acetylamino)-acetylamino]-phenyl}-2-pyrrolidin-1-yl-ethyl)-2-(3,4-dichloro-phenyl)-N-methyl-acetamide 在 1-羟基苯并三唑 、 N,N'-二环己基碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 50.5h， 以69%的产率得到N-{([(3-{(S)-α-[N-{2-(3,4-dichlorophenyl)acetyl}-N'-methylamino]-α-[pyrrolidin-1-ylmethyl]methyl}phenylaminocarbonyl)methyl]aminocarbonyl)methyl}-N'-({[(naltrindol-7'-ylaminocarbonyl)methyl]aminocarbonyl}methyl)succinamide
  参考文献：
  名称：

  A Bivalent Ligand (KDAN-18) Containing δ-Antagonist and κ-Agonist Pharmacophores Bridges δ₂ and κ₁ Opioid Receptor Phenotypes

  摘要：

  To characterize delta- and kappa-opioid receptor phenotypes, bivalent ligands (KDAN series) containing delta-antagonist (naltrindole) and kappa(1)-agonist (ICI-199,441) pharmacophores were synthesized and evaluated by the intrathecal route using the mouse tail-flick assay and binding studies. The data have suggested that KDAN-18 (2) bridges phenotypic delta(2)- and kappa(1)-receptors. A conceptual model is presented to explain the organizational differences between the opioid receptors that give rise to the phenotypes (delta(1), delta(2), kappa(1), kappa(2)).

  DOI：

  10.1021/jm034234f
• 作为产物：
  描述：

  在 palladium on activated charcoal 氢气 作用下， 以 甲醇 为溶剂， 反应 69.0h， 生成 N-((S)-1-{3-[2-(2-Amino-acetylamino)-acetylamino]-phenyl}-2-pyrrolidin-1-yl-ethyl)-2-(3,4-dichloro-phenyl)-N-methyl-acetamide
  参考文献：
  名称：

  芳基乙酰胺衍生的荧光探针：小鼠小神经胶质细胞中κ阿片受体的合成，生物学评估和直接荧光标记。

  摘要：

  2-（3,4-二氯苯基）-N-甲基-N- [1-（3-或4-氨基苯基）-2-（1-吡咯烷基）乙基]乙酰胺的荧光素异硫氰酸酯异构体I（FITC-1）共轭物（ 10和14）是在没有或有插入的单，二或四糖基接头的情况下制备的。发现3-取代的荧光探针（2-5）在平滑肌制剂中保留了有效的激动剂活性，并且在受体结合测定中具有高κ受体亲和力和选择性。4-取代的系列（6-9）的效力远低于相应的3-取代的化合物。流式细胞仪分析表明，含有四糖基接头的荧光探针5对小鼠小胶质细胞进行了直接的kappa特异性染色，如在有κ选择性拮抗剂norbinaltorphimine（norBNI）的情况下，阳性标记的细胞百分比降低41％，平均荧光强度降低61％所示。在类似的研究中，没有接头的探针2仅表现出非特异性结合。这是荧光非肽类阿片配体直接，选择性地染色κ阿片受体的首次报道。本研究的结果说明了引入亲水性连接子以减少荧光探针对阿片受体的非特异性结合的重要性。

  DOI：

  10.1021/jm950813b

文献信息

• A κ Opioid Pharmacophore Becomes a Spinally Selective κ-δ Agonist When Modified with a Basic Extender Arm
  作者：Ye Tang、Jie Yang、Mary M. Lunzer、Michael D. Powers、Philip S. Portoghese

  DOI：10.1021/ml1001294

  日期：2011.1.13

  We have explored the concept of a molecular extender arm attached to a kappa opioid agonist pharmacophore 3 (ICI-199,441) in an effort to potentially interact, with a complementary group on a neighboring opioid receptor. The containing a terminal amine group was lengthened incrementally from 11 1 up to 18 atoms. Increasing the number-of atoms in the arm produced virtually no change in the mouse intracerebroventricular (i.c.v.) antinociceptive potency In contrast, the intrathecal (i.t.) potency of 6 (KDA-16) with a 16 atom arm was dramatically increased, as reflected by its antinociceptive i.c.v./i.t. ED50 ratio of similar to 130. Further lengthening led to a decreased ED50 ratio. In vivo selective antagonist studies of KDA-16 revealed that kappa and delta opioid receptors were responsible for the greatly enhanced it potency Calcium release experiments in HEK-293 cells suggested that KDA-16 selectively activate kappa-delta heteromers. These data are consistent with the reported possible presence of heteromeric kappa-delta opioid receptors in mouse spinal cord but not in the brain. The use of a molecular extender arm may be useful for developing spinally selective analgesics.
• Arylacetamide-Derived Fluorescent Probes:  Synthesis, Biological Evaluation, and Direct Fluorescent Labeling of κ Opioid Receptors in Mouse Microglial Cells
  作者：An-Chih Chang、Chun C. Chao、Akira E. Takemori、Genya Gekker、Shuxian Hu、Phillip K. Peterson、Philip S. Portoghese

  DOI：10.1021/jm950813b

  日期：1996.1.1

  conjugates of 2-(3,4-dichlorophenyl)-N-methyl-N-[1-(3- or 4-aminophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide (10 and 14) were prepared either without or with an intervening mono-, di-, or tetraglycyl linker. The 3-substituted fluorescent probes (2-5) were found to retain potent agonist activity in smooth muscle preparations as well as high kappa receptor affinity and selectivity in receptor binding assays

  2-（3,4-二氯苯基）-N-甲基-N- [1-（3-或4-氨基苯基）-2-（1-吡咯烷基）乙基]乙酰胺的荧光素异硫氰酸酯异构体I（FITC-1）共轭物（ 10和14）是在没有或有插入的单，二或四糖基接头的情况下制备的。发现3-取代的荧光探针（2-5）在平滑肌制剂中保留了有效的激动剂活性，并且在受体结合测定中具有高κ受体亲和力和选择性。4-取代的系列（6-9）的效力远低于相应的3-取代的化合物。流式细胞仪分析表明，含有四糖基接头的荧光探针5对小鼠小胶质细胞进行了直接的kappa特异性染色，如在有κ选择性拮抗剂norbinaltorphimine（norBNI）的情况下，阳性标记的细胞百分比降低41％，平均荧光强度降低61％所示。在类似的研究中，没有接头的探针2仅表现出非特异性结合。这是荧光非肽类阿片配体直接，选择性地染色κ阿片受体的首次报道。本研究的结果说明了引入亲水性连接子以减少荧光探针对阿片受体的非特异性结合的重要性。
• A Bivalent Ligand (KDAN-18) Containing δ-Antagonist and κ-Agonist Pharmacophores Bridges δ₂ and κ₁ Opioid Receptor Phenotypes
  作者：David J. Daniels、Amol Kulkarni、Zhihua Xie、Rashmi G. Bhushan、Philip S. Portoghese

  DOI：10.1021/jm034234f

  日期：2005.3.1

  To characterize delta- and kappa-opioid receptor phenotypes, bivalent ligands (KDAN series) containing delta-antagonist (naltrindole) and kappa(1)-agonist (ICI-199,441) pharmacophores were synthesized and evaluated by the intrathecal route using the mouse tail-flick assay and binding studies. The data have suggested that KDAN-18 (2) bridges phenotypic delta(2)- and kappa(1)-receptors. A conceptual model is presented to explain the organizational differences between the opioid receptors that give rise to the phenotypes (delta(1), delta(2), kappa(1), kappa(2)).