Dynorphin A-(1-11) amide | 79985-48-1

• 分子结构分类: 有机化合物 - 有机聚合物 - 多肽
• 英文名称: Dynorphin A-(1-11) amide
• 英文别名: H-Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-NH₂；Dyn A(1-11)-NH₂；dynorphin 1-11；DP-11-00；Dynorphin A (1-11) amide；(2S)-1-[(2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]acetyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]-N-[(2S)-1,6-diamino-1-oxohexan-2-yl]pyrrolidine-2-carboxamide
• CAS: 79985-48-1
• 化学式: C₆₃H₁₀₄N₂₂O₁₂
• 分子量: 1361.66
• InChiKey: OKJAOUBQLSWUNX-QFIUEGLPSA-N

物化性质

• 密度：
  1.42±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -2.8
• 重原子数：
  97
• 可旋转键数：
  44
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  591
• 氢给体数：
  19
• 氢受体数：
  17

反应信息

• 作为产物：
  描述：

  BOC-L-脯氨酸 、 BOC-L-异亮氨酸 、 N-叔丁氧羰基-N'-甲苯磺酰基-L-精氨酸 、 N^α-Boc-N^ε-(2,4-dichlorobenzyloxycarbonyl)-L-lysine 、 alkaline earth salt of/the/ methylsulfuric acid 生成 Dynorphin A-(1-11) amide
  参考文献：
  名称：

  强啡肽A（1-11）-NH2 3位残基的修饰对κ受体选择性和效能的影响。

  摘要：

  据报道强啡肽A（Dyn A）中的酪氨酸1和苯丙氨酸4是阿片激动剂活性和对κ受体效力的重要残基。强啡肽A在2和3位的甘氨酸残基可能会影响1和4位芳环的相对取向，但它们的柔韧性妨碍了仔细的分析。为了检查对强啡肽A的这些作用，我们先前已经合成了线性类似物[D-Ala3] Dyn A（1-11）-NH2（2）和[Ala3] Dyn A（1-11）-NH2（3），并进行了报道他们的生物活动。类似物2和3与Dyn A（1-11）-NH2（1）（IC50 = 0.58 nM）相似，显示出对中央κ阿片受体的亲和力（分别为IC50 = 0.76和1.1 nM）（IC50 = 0.58 nM），并且大大提高了对Kappa的选择性vs mu和kappa vs delta受体（2的IC50比分别为350和1300，3的IC50比为190和660，分别）。这些结果表明，Dyn A（1-11）-NH2 3位氨基酸的结

  DOI：

  10.1021/jm950655o

文献信息

• Design, Synthesis, and Biological Activities of Cyclic Lactam Peptide Analogues of Dynorphin A(1−11)-NH₂
  作者：Feng-Di T. Lung、Nathan Collins、Dagmar Stropova、Peg Davis、Henry I. Yamamura、Frank Porreca、Victor J. Hruby

  DOI：10.1021/jm950369c

  日期：1996.1.1

  selectivity for kappa opioid receptors. Positions 2-6, 3-7, and 5-9 were chosen as the sites for incorporating cyclic conformational constraints. Cyclization between D-Asp(2) and Lys(6) in c[D-Asp(2),Lys(6)]Dyn A(1-11)-NH2 led to an analogue with pronounced potency and selectivity enhancement for the mu opioid receptor, whereas cyclization between D-Asp(3) and Lys(7) in c[D-Asp(3),Lys(7)]Dyn A(1-11)-NH2 led to

  我们以前已经报道了使用分子力学能量最小化方法由地址序列诱导的强啡肽A（Dyn A）与中央κ阿片受体的四种可能的结合构象。发现最低的能量构象在环化的地址序列中表现出α-螺旋构象。有人提出，环化地址序列中的α-螺旋构象或由消息序列的构象特征诱导的螺旋构象对于结合力和κ阿片受体选择性可能是重要的。在i和i + 4位之间的侧链至侧链内酰胺桥已显示稳定α-螺旋构象。因此，设计了一系列强啡肽A（1-11）-NH2的环状内酰胺类似物，通过豚鼠脑（GPB）结合测定法和豚鼠回肠（GPI）生物测定法合成和评估，以评估构象分析预测，并进一步研究对κ阿片受体具有高效能和选择性的构象要求。选择位置2-6、3-7和5-9作为合并循环构象约束的位点。在c [D-Asp（2），Lys（6）] Dyn A（1-11）-NH2中D-Asp（2）和Lys（6）之间的环化导致类似物具有明显的效能和对mu的选择性增强阿片受体，而c
• The Effects of C-Terminal Modifications on the Opioid Activity of [<i>N</i>-BenzylTyr¹]Dynorphin A-(1−11) Analogues
  作者：Kshitij A. Patkar、Thomas F. Murray、Jane V. Aldrich

  DOI：10.1021/jm900715m

  日期：2009.11.12

  peptide dynorphin (Dyn) A have focused on the N-terminal “message” sequence based on the “message-address” concept. To test the hypothesis that changes in the C-terminal “address” domain could affect efficacy, modified amino acids and cyclic constraints were incorporated into this region of the partial agonist [N-benzylTyr1]Dyn A-(1−11). Modifications in the C-terminal domain of [N-benzylTyr1]Dyn A-(1−11)NH2

  影响内源性阿片肽强啡肽 (Dyn) A 类似物功效的结构修饰侧重于基于“消息地址”概念的 N 端“消息”序列。为了检验 C 端“地址”结构域的变化可能影响功效的假设，将修饰的氨基酸和循环约束并入部分激动剂 [ N- benzylTyr 1 ]Dyn A-(1-11) 的该区域。[ N- benzylTyr 1 ]Dyn A-(1−11)NH 2的 C 端结构域中的修饰导致所有线性类似物的 κ 阿片受体 (KOR) 亲和力增加，但不影响这些肽在韩国。位置 5 和 8 之间的环化产生 [ N-benzylTyr 1 , cyclo ( d -Asp 5 ,Dap 8 )]Dyn A-(1−11)NH 2 (zyklophin, 13 ) ( J. Med. Chem. 2005 , 48 , 4500−4503) 对 KOR 具有高选择性. 与线性肽相比，该肽在腺苷酸环化酶 (AC) 测定中的功效可忽略不计，并且是
• [2‘,6‘-Dimethyltyrosine]Dynorphin A(1−11)-NH₂ Analogues Lacking an N-Terminal Amino Group:  Potent and Selective κ Opioid Antagonists
  作者：Yixin Lu、Thi M.-D. Nguyen、Grazyna Weltrowska、Irena Berezowska、Carole Lemieux、Nga N. Chung、Peter W. Schiller

  DOI：10.1021/jm0101186

  日期：2001.9.1

  analogues containing two methyl groups at the 2',6'-positions of the Tyr(1) aromatic ring and lacking an N-terminal amino group were moderately potent delta and mu opioid antagonists. These results indicate that a positively charged N-terminal amino group may be essential for signal transduction but not for receptor binding and suggested that its deletion in agonist opioid peptides containing an N-terminal

  最近的研究表明，在吗啡和脑啡肽类似物的Tyr（1）芳香环的2'，6'-位置上含有两个甲基，并且缺乏N端氨基，它们是中等强度的δ和μ阿片类拮抗剂。这些结果表明，带正电荷的N末端氨基对于信号转导可能是必不可少的，但对于受体结合却不是，并且表明其在包含N末端2'，6'-二甲基酪氨酸（Dmt）残基的激动剂阿片肽中的缺失可能代表将它们转变为拮抗剂的一般方法。为了开发强啡肽A（Dyn A）衍生的κ阿片拮抗剂，我们制备了[Dmt（1）] Dyn A（1-11）-NH2（1）的类似物，其中N端氨基为省略或被甲基取代。这是通过将Tyr（1）替换为3-（2，6-二甲基-4-羟基苯基）丙酸（Dhp）或（2S）-2-甲基-3-（2,6-二甲基-4-羟基苯基）丙酸[（2S）-Mdp]。在豚鼠回肠和小鼠输精管生物测定以及大鼠和豚鼠脑膜受体结合测定中测试了化合物。事实证明，所有类似物都是针对Dyn A（1-13）和非肽激动剂U50
• Design, Synthesis, and Biological Properties of highly Potent Cyclic Dynorphin A Analogs. Analogs Cyclized between Positions 5 and 11
  作者：Jean-Philippe Meyer、Nathan Collins、Feng-Di Lung、Peg Davis、Teresa Zalewska、Frank Porreca、Henry I. Yamamura、Victor J. Hruby

  DOI：10.1021/jm00049a010

  日期：1994.11

  We have recently reported the synthesis of several cyclic disulfide bridge-containing peptide analogues of dynorphin A (Dyn A), which were conformationally constrained in the putative address segment of the opioid ligand. Several of these analogues, bridged between positions 5 and 11 of Dyn A(1-11)-NH2, exhibited unexpected selectivities for the kappa and mu receptors of the central over the peripheral nervous systems. In order to further investigate the conformational and topographical requirements for the residues in positions 5 and 11 of these analogues, we have synthesized a systematic series of Dyn A(1-11)-NH2 analogues incorporating the sulfydryl containing amino acids L- and D-Cys and L- and D-Pen in positions 5 and 11, thus producing 16 cyclic peptides. In addition, Dyn A(1-11)-NH2, [D-Leu(5)]Dyn A(1-11)-NH2, and [D-Lys(11)]Dyn A(1-11)-NH2 were synthesized as standards. Several of these cyclic analogues, especially c[Cys(5), D-Cys(11)] Dyn A(1-11)-NH2, c[Cys(5), L- or D-Pen(11)]Dyn A(1-11)-NH2, c[Pen(5), L-Pen(11)]Dyn A(1-11)-NH2 and c[Pen(5), L- or D-Cys(11)]Dyn A(1-11)-NH2, retained the same affinity and selectivity (vs the mu and delta receptors) as the parent compound Dyn A(1-11)-NH2 in the guinea pig brain (GPB). These same analogues and most others exhibited a much lower activity in the guinea pig ileum (GPI), thus leading to centrally vs peripherally selective peptides, but showed a different structure-activity relationship than found previously. In a wider scope, this series of analogues also provided new insights into which amino acids (and their configurations) may be used in positions 5 and 11 of Dyn A analogues for high potency and good selectivity at kappa opioid receptors. The results obtained in the GPB suggest that requirements for binding are not the same for the kappa, mu, or delta central receptors.
• Design and synthesis of highly potent and selective cyclic dynorphin A analogs
  作者：Andrew M. Kawasaki、Richard J. Knapp、Thomas H. Kramer、William S. Wire、Olga S. Vasquez、Henry I. Yamamura、Thomas F. Burks、Victor J. Hruby

  DOI：10.1021/jm00169a007

  日期：1990.7

  We have designed and synthesized several cyclic disulfide-containing peptide analogues of dynorphin A (Dyn A) which are conformationally constrained in the putative "address" segment of the opioid ligand. Several of these Dyn A analogues exhibit unexpected selectivities for the kappa and mu opioid receptors(s) of the central vs peripheral nervous systems. Thus, incorporation of conformational constraint in the putative "address" segment of Dyn A analogues has resulted in the kappa/mu opioid receptor ligands [Cys5,Cys11]Dyn A1-11-NH2 (1) and [Cys5,Cys11,D-Ala8]Dyn A1-11-NH2 (2), which possess high kappa and mu opioid receptor affinities centrally (guinea pig brain, GPB), but only weak activity at peripheral kappa and mu opioid receptors (guinea pig ileum, GPI). On the other hand, [Cys8,Cys13]Dyn A1-13-NH2 and [D-Cys8,D-Cys13]Dyn A1-13-NH2 (5) display high kappa potencies and selectivities at the peripheral (GPI) but not at the central (GPB) kappa opioid receptor. The lack of correlation between the pharmacological profiles observed in smooth muscle and in the brain binding assays suggests the existence of different subtypes of the kappa and mu opioid receptors in the brain and peripheral nervous systems.