400-998-5282
专注多肽 服务科研
400-998-5282
专注多肽 服务科研
Dynorphin A acetate是一种七肽，来源于前炔诺啡的裂解，广泛分布于中枢神经系统。它作为内源性κ受体激动剂，具有纳摩尔结合亲和力。
编号：114465
CAS号：80448-90-4
单字母：H2N-YGGFLRRIRPKLKWDNQ-OH
| 参考文献（References）: | A. Goldstein et al., PNAS, 78, 7219 (1981) S. Tachibana et al., Nature, 295, 339 (1982) A.I. Faden, J. Neurosci., 12, 425 (1992) |
| 溶解度: | Soluble in water |
Dynorphin A acetate是一种七肽，来源于前炔诺啡的裂解，广泛分布于中枢神经系统。它作为内源性κ受体激动剂，具有纳摩尔结合亲和力。它还激活ORL1的人类新型阿片受体样受体。它对酶降解具有抗性，并可能具有抗伤害的功能。
Dynorphin A acetate is a heptadecapeptide derived from the cleavage of prodynorphin and found widely distributed in the central nervous system. It acts as an endogenous kappa receptor agonist with nanomolar binding affinity. It also activates the human novel opioid receptor-like receptor of ORL1. It is resistant to enzymatic degradation and may have antinociceptive functions.
Dynorphins是一类阿片肽，由前体蛋白proynorphin产生。在被前蛋白转化酶2（PC2）切割后，释放出多种活性肽：强啡肽A、强啡肽B和α/β-新内啡肽。Dynorphins主要通过阿片受体（KOR）发挥作用，KOR是一种G蛋白偶联受体。强啡肽已被证明是疼痛反应的调节剂，参与药物成瘾和食欲控制。
Dynorphins are a class of opioid peptides that arise from the precursor protein prodynorphin. Upon cleavage by proprotein convertase 2 (PC2), multiple active peptides are released: dynorphin A, dynorphin B, and α/β-neo-endorphin. Dynorphins exert their effects primarily through the Κ-opioid receptor (KOR), a G-protein-coupled receptor. Dynorphin has been shown to be a modulator of pain response, involved in drug addiction and appetite control.
强啡肽（209-225）。阿片受体激动剂。
Prodynorphin (209-225). Opioid receptor agonist.
强啡肽A是一种属于强啡肽家族的肽，对所有三种阿片受体都有亲和力。然而，已经发现强啡肽A有利于κ阿片受体，这些受体在大脑、外周组织和脊髓中表达，位于疼痛相关区域。例如，当强啡肽A与κ阿片受体结合时，多巴胺在药物成瘾中普遍存在的大脑区域受到抑制，从而证明强啡肽A对大脑奖励回路具有拮抗作用。强啡肽A可能成为研究镇痛、奖励和成瘾的有用研究工具。
Dynorphin A is a peptide that belongs to the dynorphin family and has affinity for all three of the opioid receptors. However it has been found that Dynorphin A favors kappa-opioid receptors which are expressed in the brain, peripheral tissues and the spinal cord and are located in areas involved in pain. For example when Dynorphin A binds to kappa-opioid receptors, dopamine is inhibited in areas of the brain prevalent in drug addiction, thus demonstrated Dynorphin A to have antagonistic effects on the brain reward circuit. Dynorphin A could be a useful research tool for studying analgesia, reward and addiction.
强啡肽 A（1‑17）是全长阿片片段，常用于分析延伸受体相互作用域。其序列适用于芳香簇与碱性残基贡献定位。研究者通过探究其动
Dynorphin A 强啡肽 A 是一种内源性阿片肽，参与中枢神经系统 (CNS) 的抑制性神经调节。强啡肽 A 是一种高效的 kappa 阿片受体 ( KOR ) 激动剂，也是其他阿片受体的激动剂，如mu (MOR)和delta (DOR)。强啡肽A可诱导神经元死亡，可用于神经系统疾病的相关研究。
强啡肽的定义
强啡肽是一类内源性阿片肽，在大脑的许多不同部位产生，包括下丘脑、海马和脊髓，根据产生部位的不同，具有许多不同的生理作用。
Dynorphins are a class of endogenous opioid peptides produced in many different parts of the brain, including the hypothalamus, the hippocampus and the spinal cord, and have many different physiological actions, depending upon the site of production.
强啡肽的相关多肽
Dynorphins来源于前体蛋白proynorphin。当前强啡肽在加工过程中被前蛋白转化酶2（PC2）切割时，会释放出多种活性肽：强啡肽A、强啡肽B、“大强啡肽”和A/β-新强啡肽1。
Dynorphins arise from the precursor protein prodynorphin. When prodynorphin is cleaved during processing by proprotein convertase 2 (PC2), multiple active peptides are released: dynorphin A, dynorphin B, “big dynorphin” and a/ß-neo-endorphin【1】.
强啡肽的发现
Dynophin于20世纪70年代中期在阿片受体和内源性阿片肽领域最重要的研究人员之一Avram Goldstein的实验室中被发现。Goldstein与日本生物化学家Shinro Tachibana合作进行了分子鉴定，以进行纯化，M.Hunkapiller和L.Hood进行了微测序。
Dynophin was discovered in the mid 1970's in the laboratory of Avram Goldstein, one of the most important researchers in the field of opioid receptors and endogenous opioid peptides. The molecular identification was achieved by Goldstein in collaboration with the Japanese biochemist, Shinro Tachibana for purification, and M. Hunkapiller and L. Hood, who performed the microsequencing.
强啡肽的结构特点
从猪垂体中分离出一种4000道尔顿的强啡肽（也称为“大强啡肽”）。它有32个氨基酸，氨基末端有一个称为强啡肽a的十七肽（17个氨基酸序列），羧基末端有一种相关的十三肽（13个氨基酸序列，强啡肽B）。这两种肽由“处理信号”Lys-Arg【2】分离。
A 4,000-dalton dynorphin (also called the “Big dynorphin”) was isolated from porcine pituitary. It has 32 amino acids, with a heptadecapeptide (17 amino acid sequence), called dynorphin A, at its amino terminus and a related tridecapeptide (13 amino acid sequence), dynorphin B, at its carboxyl terminus. The two peptides are separated by the "processing signal" Lys-Arg【2】.
强啡肽的作用机制
Dynorphins主要通过一种名为？的G蛋白偶联受体发挥作用？-阿片受体（KOR）【3】。尽管KOR是所有强啡肽的主要受体，但这些肽确实对µ-阿片受体（MOR）、d-阿片受体、N-甲基-d-天冬氨酸（NMDA）型谷氨酸受体和缓激肽受体有一定的亲和力。不同的强啡肽在受体上表现出不同的受体选择性和效力。强啡肽和强啡肽A都比强啡肽B更有效、更具选择性。强啡肽通过与多巴胺神经末梢上的KOR结合来减少多巴胺的释放，从而导致药物耐受和戒断症状。
Dynorphins primarily exert their effects through a G-protein coupled receptor called the ?-opioid receptor (KOR)【3】 Although KOR is the primary receptor for all dynorphins, the peptides do have some affinity for the µ-opioid receptor (MOR), d-opioid receptor (DOR), N-methyl-D-aspartic acid (NMDA)-type glutamate receptor, and bradykinin receptor. Different dynorphins show different receptor selectivities and potencies at receptors. Both big dynorphin and dynorphin A are more potent and more selective than dynorphin B. Dynorphin decreases dopamine release by binding to KORs on dopamine nerve terminals, which leads to drug tolerance and withdrawal symptoms.
强啡肽的功能
Dynorphins调节疼痛反应。它们可以显著抑制吗啡或β-内啡肽诱导的镇痛作用【4】。Dynorphins抑制多巴胺的释放，这会抵消可卡因的愉悦作用【5】。它们通过控制食欲和昼夜节律来维持体内平衡【6】。除了在控制体重方面的作用外，还发现强啡肽可以调节体温【7】。
Dynorphins modulate pain response. They can significantly inhibit morphine- or beta-endorphin-induced analgesia【4】. Dynorphins inhibit dopamine release that would counter the pleasurable effects of cocaine【5】. They are important in maintaining homeostasis through appetite control and circadian rhythms【6】. In addition to their role in weight control, dynorphins have also been found to regulate body temperature【7】.
References
1. Day, R., Lazure, C., Basak, A., Boudreault, A., Limperis, P., Dong, W., et al. (1998). Prodynorphin processing by proprotein convertase 2. Cleavage at single basic residues and enhanced processing in the presence of carboxypeptidase activity. J Biol. Chem., 273(2), 829-836.
2. W Fischli, A Goldstein, M W Hunkapiller, and L E Hood (1982). Isolation and amino acid sequence analysis of a 4,000-dalton dynorphin from porcine pituitary. PNAS, 79 (17), 5435-5437.
3. Nyberg, F. & Hallburg, M. (2007). Neuropeptides in hyperthermia. Progress in brain research, 162:277-93.
4. FC Tulunay, MF Jen, JK Chang, HH Loh and NM Lee, (1981). Possible regulatory role of dynorphin on morphine- and beta-endorphin- induced analgesia. American Society for Pharmacology and Experimental Therapeutics, 219 (2), 296-298.
5. Clavin, W. (2005). Dynorphin: Nature’s Own Antidote to Cocaine (and Pleasure?).
6. Przewlocki, R., Lason, W., Konecka, A. M., Gramsch, C., Herz, A., & Reid, L. D. (1983). The opioid peptide dynorphin, circadian rhythms, and starvation. Science, 219(4580), 71-73.
7. Xin, L., Geller, E. B., & Adler, M. W. (1997). Body temperature and analgesic effects of selective mu and kappa opioid receptor agonists microdialyzed into rat brain. Journal of Pharmacology and Experimental Therapeutics, 281(1), 499-507.
| DOI | 名称 | |
|---|---|---|
| 10.1124/mol.55.2.324 | Distinct mechanisms for activation of the opioid receptor-like 1 and kappa-opioid receptors by nociceptin and dynorphin A | 下载 |
| 10.1038/295339a0 | Isolation and structure of dynorphin, an opioid peptide, from porcine duodenum | 下载 |
| 10.1016/s0306-4522(99)00472-8 | The kappa opioid receptor and dynorphin co-localize in vasopressin magnocellular neurosecretory neurons in guinea-pig hypothalamus | 下载 |
多肽H2N-Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gln-COOH的合成步骤：
1、合成CTC树脂：称取0.36g CTC Resin（如初始取代度约为0.95mmol/g）和0.41mmol Fmoc-Gln(Trt)-OH于反应器中，加入适量DCM溶解氨基酸（需要注意，此时CTC树脂体积会增大好几倍，避免DCM溶液过少），再加入1.03mmol DIPEA（Mw：129.1,d：0.740g/ml），反应2-3小时后，可不抽滤溶液，直接加入1ml的HPLC级甲醇，封端半小时。依次用DMF洗涤2次，甲醇洗涤1次，DCM洗涤一次，甲醇洗涤一次，DCM洗涤一次，DMF洗涤2次（这里使用甲醇和DCM交替洗涤，是为了更好地去除其他溶质，有利于后续反应）。得到 Fmoc-Gln(Trt)-CTC Resin。结构图如下：
2、脱Fmoc：加3倍树脂体积的20%Pip/DMF溶液，鼓氮气30分钟，然后2倍树脂体积的DMF 洗涤5次。得到 H2N-Gln(Trt)-CTC Resin 。（此步骤脱除Fmoc基团，茚三酮检测为蓝色，Pip为哌啶）。结构图如下：
3、缩合：取1.03mmol Fmoc-Asn(Trt)-OH 氨基酸，加入到上述树脂里，加适当DMF溶解氨基酸，再依次加入2.05mmol DIPEA，0.97mmol HBTU。反应30分钟后，取小样洗涤，茚三酮检测为无色。用2倍树脂体积的DMF 洗涤3次树脂。（洗涤树脂，去掉残留溶剂，为下一步反应做准备）。得到Fmoc-Asn(Trt)-Gln(Trt)-CTC Resin。氨基酸：DIPEA：HBTU：树脂=3：6：2.85：1（摩尔比）。结构图如下：
4、依次循环步骤二、步骤三，依次得到
H2N-Asn(Trt)-Gln(Trt)-CTC Resin
Fmoc-Asp(OtBu)-Asn(Trt)-Gln(Trt)-CTC Resin
H2N-Asp(OtBu)-Asn(Trt)-Gln(Trt)-CTC Resin
Fmoc-Trp(Boc)-Asp(OtBu)-Asn(Trt)-Gln(Trt)-CTC Resin
H2N-Trp(Boc)-Asp(OtBu)-Asn(Trt)-Gln(Trt)-CTC Resin
Fmoc-Lys(Boc)-Trp(Boc)-Asp(OtBu)-Asn(Trt)-Gln(Trt)-CTC Resin
H2N-Lys(Boc)-Trp(Boc)-Asp(OtBu)-Asn(Trt)-Gln(Trt)-CTC Resin
Fmoc-Leu-Lys(Boc)-Trp(Boc)-Asp(OtBu)-Asn(Trt)-Gln(Trt)-CTC Resin
H2N-Leu-Lys(Boc)-Trp(Boc)-Asp(OtBu)-Asn(Trt)-Gln(Trt)-CTC Resin
Fmoc-Lys(Boc)-Leu-Lys(Boc)-Trp(Boc)-Asp(OtBu)-Asn(Trt)-Gln(Trt)-CTC Resin
H2N-Lys(Boc)-Leu-Lys(Boc)-Trp(Boc)-Asp(OtBu)-Asn(Trt)-Gln(Trt)-CTC Resin
Fmoc-Pro-Lys(Boc)-Leu-Lys(Boc)-Trp(Boc)-Asp(OtBu)-Asn(Trt)-Gln(Trt)-CTC Resin
H2N-Pro-Lys(Boc)-Leu-Lys(Boc)-Trp(Boc)-Asp(OtBu)-Asn(Trt)-Gln(Trt)-CTC Resin
Fmoc-Arg(Pbf)-Pro-Lys(Boc)-Leu-Lys(Boc)-Trp(Boc)-Asp(OtBu)-Asn(Trt)-Gln(Trt)-CTC Resin
H2N-Arg(Pbf)-Pro-Lys(Boc)-Leu-Lys(Boc)-Trp(Boc)-Asp(OtBu)-Asn(Trt)-Gln(Trt)-CTC Resin
Fmoc-Ile-Arg(Pbf)-Pro-Lys(Boc)-Leu-Lys(Boc)-Trp(Boc)-Asp(OtBu)-Asn(Trt)-Gln(Trt)-CTC Resin
H2N-Ile-Arg(Pbf)-Pro-Lys(Boc)-Leu-Lys(Boc)-Trp(Boc)-Asp(OtBu)-Asn(Trt)-Gln(Trt)-CTC Resin
Fmoc-Arg(Pbf)-Ile-Arg(Pbf)-Pro-Lys(Boc)-Leu-Lys(Boc)-Trp(Boc)-Asp(OtBu)-Asn(Trt)-Gln(Trt)-CTC Resin
H2N-Arg(Pbf)-Ile-Arg(Pbf)-Pro-Lys(Boc)-Leu-Lys(Boc)-Trp(Boc)-Asp(OtBu)-Asn(Trt)-Gln(Trt)-CTC Resin
Fmoc-Arg(Pbf)-Arg(Pbf)-Ile-Arg(Pbf)-Pro-Lys(Boc)-Leu-Lys(Boc)-Trp(Boc)-Asp(OtBu)-Asn(Trt)-Gln(Trt)-CTC Resin
H2N-Arg(Pbf)-Arg(Pbf)-Ile-Arg(Pbf)-Pro-Lys(Boc)-Leu-Lys(Boc)-Trp(Boc)-Asp(OtBu)-Asn(Trt)-Gln(Trt)-CTC Resin
Fmoc-Leu-Arg(Pbf)-Arg(Pbf)-Ile-Arg(Pbf)-Pro-Lys(Boc)-Leu-Lys(Boc)-Trp(Boc)-Asp(OtBu)-Asn(Trt)-Gln(Trt)-CTC Resin
H2N-Leu-Arg(Pbf)-Arg(Pbf)-Ile-Arg(Pbf)-Pro-Lys(Boc)-Leu-Lys(Boc)-Trp(Boc)-Asp(OtBu)-Asn(Trt)-Gln(Trt)-CTC Resin
Fmoc-Phe-Leu-Arg(Pbf)-Arg(Pbf)-Ile-Arg(Pbf)-Pro-Lys(Boc)-Leu-Lys(Boc)-Trp(Boc)-Asp(OtBu)-Asn(Trt)-Gln(Trt)-CTC Resin
H2N-Phe-Leu-Arg(Pbf)-Arg(Pbf)-Ile-Arg(Pbf)-Pro-Lys(Boc)-Leu-Lys(Boc)-Trp(Boc)-Asp(OtBu)-Asn(Trt)-Gln(Trt)-CTC Resin
Fmoc-Gly-Phe-Leu-Arg(Pbf)-Arg(Pbf)-Ile-Arg(Pbf)-Pro-Lys(Boc)-Leu-Lys(Boc)-Trp(Boc)-Asp(OtBu)-Asn(Trt)-Gln(Trt)-CTC Resin
H2N-Gly-Phe-Leu-Arg(Pbf)-Arg(Pbf)-Ile-Arg(Pbf)-Pro-Lys(Boc)-Leu-Lys(Boc)-Trp(Boc)-Asp(OtBu)-Asn(Trt)-Gln(Trt)-CTC Resin
Fmoc-Gly-Gly-Phe-Leu-Arg(Pbf)-Arg(Pbf)-Ile-Arg(Pbf)-Pro-Lys(Boc)-Leu-Lys(Boc)-Trp(Boc)-Asp(OtBu)-Asn(Trt)-Gln(Trt)-CTC Resin
H2N-Gly-Gly-Phe-Leu-Arg(Pbf)-Arg(Pbf)-Ile-Arg(Pbf)-Pro-Lys(Boc)-Leu-Lys(Boc)-Trp(Boc)-Asp(OtBu)-Asn(Trt)-Gln(Trt)-CTC Resin
Fmoc-Tyr(tBu)-Gly-Gly-Phe-Leu-Arg(Pbf)-Arg(Pbf)-Ile-Arg(Pbf)-Pro-Lys(Boc)-Leu-Lys(Boc)-Trp(Boc)-Asp(OtBu)-Asn(Trt)-Gln(Trt)-CTC Resin
以上中间结构，均可在专肽生物多肽计算器-多肽结构计算器中，一键画出。
最后再经过步骤二得到 H2N-Tyr(tBu)-Gly-Gly-Phe-Leu-Arg(Pbf)-Arg(Pbf)-Ile-Arg(Pbf)-Pro-Lys(Boc)-Leu-Lys(Boc)-Trp(Boc)-Asp(OtBu)-Asn(Trt)-Gln(Trt)-CTC Resin，结构如下：
5、切割：6倍树脂体积的切割液（或每1g树脂加8ml左右的切割液），摇床摇晃 2小时，过滤掉树脂，用冰无水乙醚沉淀滤液，并用冰无水乙醚洗涤沉淀物3次，最后将沉淀物放真空干燥釜中，常温干燥24小试，得到粗品H2N-Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gln-COOH。结构图见产品结构图。
切割液选择：1）TFA：H2O=95%：5%
2）TFA：H2O：TIS=95%：2.5%：2.5%
3）三氟乙酸：茴香硫醚：1，2-乙二硫醇：苯酚：水=87.5%：5%：2.5%：2.5%：2.5%
（前两种适合没有容易氧化的氨基酸，例如Trp、Cys、Met。第三种适合几乎所有的序列。）
6、纯化冻干：使用液相色谱纯化，收集目标峰液体，进行冻干，获得蓬松的粉末状固体多肽。不过这时要取小样复测下纯度 是否目标纯度。
7、最后总结：
杭州专肽生物技术有限公司（ALLPEPTIDE https://www.allpeptide.com）主营定制多肽合成业务，提供各类长肽，短肽，环肽，提供各类修饰肽，如：荧光标记修饰（CY3、CY5、CY5.5、CY7、FAM、FITC、Rhodamine B、TAMRA等），功能基团修饰肽（叠氮、炔基、DBCO、DOTA、NOTA等），同位素标记肽（N15、C13），订书肽（Stapled Peptide）,脂肪酸修饰肽（Pal、Myr、Ste），磷酸化修饰肽（P-Ser、P-Thr、P-Tyr），环肽（酰胺键环肽、一对或者多对二硫键环），生物素标记肽，PEG修饰肽，甲基化修饰肽等。
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