Dihexa (PNB-0408)
(Synonyms: 益智二肽) 目录号 : GC30768
Dihexa (PNB-0408)（N-己酸-Tyr-Ile-(6)-氨基己酰胺）是一种具有口服活性、可透过血脑屏障的血管紧张素 IV 类似物。
Cas No.:1401708-83-5
Sample solution is provided at 25 µL, 10mM.
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Dihexa (PNB-0408) (N-hexanoic-Tyr-Ile-(6)-amino hexanoic amide) is an oral active, blood-brain barrier-permeable angiotensin IV analogue. Dihexa (PNB-0408) is a synthetically derived Angiotensin IV analog that is blood-brain barrier permeable, stable, and orally bioavailable[1].
Under Dihexa (PNB-0408) stimulation, the hepatocyte growth factor (HGF)/c-Met receptor system can induce dendritic dendrites and synaptogenesis[2]. The hepatoblasts were differentiated into HLCs by Dihexa and dexamethasone[3]. Dihexa(PNB-0408)( 0.1 μM) combining Vitamin C, and Forskolin (VDF) could substitute growth factors to induce hepatic specification[4]. Dihexa (PNB-0408) at both concentrations(10-10 M and 10-12 M; 30 minutes; room temperature) markedly augmented the capacity of HGF to activate c-Met[5].
Dihexa (PNB-0408) (1.44/2.88 mg/kg ;i.g.; 3 months) restored AngIV decline in APP/PS1 mice, saved the cognitive function of mice, improved neuronal loss in mice and reduced neuroinflammation and inhibited glial activation in the mouse brain[6]. Dihexa (PNB-0408)(10-6M-10-13M;30 min) protects lateral line hair cells from aminoglycoside ototoxicity. Dihexa does not alter the entry of aminoglycosides into hair cells but rather attenuates cell death through an HGF-dependent signaling mechanism [7]. Dihexa (PNB-0408) (2-4mg/kg;b.wt.;16 weeks) is promising candidates for adjunct therapies to promote limb functional recovery after surgical nerve repair, and have implications in peripheral nerve injury and limb transplantation[8].
References:
[1]. McCoy AT, Benoist CC, et,al. Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents. J Pharmacol Exp Ther. 2013 Jan;344(1):141-54. doi: 10.1124/jpet.112.199497. Epub 2012 Oct 10. PMID: 23055539; PMCID: PMC3533412.
[2]. Wright JW, Harding JW. The Brain Hepatocyte Growth Factor/c-Met Receptor System: A New Target for the Treatment of Alzheimer's Disease. J Alzheimers Dis. 2015;45(4):985-1000. doi: 10.3233/JAD-142814. PMID: 25649658.
[3]. Mathapati S, Siller R, et,al. Small-Molecule-Directed Hepatocyte-Like Cell Differentiation of Human Pluripotent Stem Cells. Curr Protoc Stem Cell Biol. 2016 Aug 17;38:1G.6.1-1G.6.18. doi: 10.1002/cpsc.13. PMID: 27532814.
[4]. Pan T, Wang N, et,al. Efficiently generate functional hepatic cells from human pluripotent stem cells by complete small-molecule strategy. Stem Cell Res Ther. 2022 Apr 11;13(1):159. doi: 10.1186/s13287-022-02831-1. PMID: 35410439; PMCID: PMC8996222.
[5]. Benoist CC, Kawas LH, et,al.The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-met system. J Pharmacol Exp Ther. 2014 Nov;351(2):390-402. doi: 10.1124/jpet.114.218735. Epub 2014 Sep 3. PMID: 25187433; PMCID: PMC4201273.
[6]. Sun X, Deng Y,et,al. AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway. Brain Sci. 2021 Nov 11;11(11):1487. doi: 10.3390/brainsci11111487. PMID: 34827486; PMCID: PMC8615599.
[7]. Uribe PM, Kawas LH, et,al. Hepatocyte growth factor mimetic protects lateral line hair cells from aminoglycoside exposure. Front Cell Neurosci. 2015 Jan 28;9:3. doi: 10.3389/fncel.2015.00003. PMID: 25674052; PMCID: PMC4309183.
[8]: Weiss JB, Phillips CJ, et,al.Stem cell, Granulocyte-Colony Stimulating Factor and/or Dihexa to promote limb function recovery in a rat sciatic nerve damage-repair model: Experimental animal studies. Ann Med Surg (Lond). 2021 Oct 8;71:102917. doi: 10.1016/j.amsu.2021.102917. PMID: 34703584; PMCID: PMC8524106.
Dihexa (PNB-0408)（N-己酸-Tyr-Ile-(6)-氨基己酰胺）是一种具有口服活性、可透过血脑屏障的血管紧张素 IV 类似物。 Dihexa (PNB-0408) 是一种合成衍生的血管紧张素 IV 类似物，具有血脑屏障渗透性、稳定性和口服生物利用度[1]。
在 Dihexa (PNB-0408) 刺激下，肝细胞生长因子 (HGF)/c-Met 受体系统可诱导树突状树突和突触发生[2]。 Dihexa和地塞米松[3]将成肝细胞分化为HLCs。 Dihexa(PNB-0408)( 0.1 μM) 结合维生素 C 和 Forskolin (VDF) 可以替代生长因子诱导肝脏规范化[4]。 Dihexa (PNB-0408) 在两个浓度（10-10 M 和 10-12 M；30 分钟；室温）下显着增强 HGF 激活 c-Met[5] 的能力。
Dihexa (PNB-0408)（1.44/2.88 mg/kg ；i.g.；3 个月）恢复 APP/PS1 小鼠的 AngIV 下降，挽救小鼠的认知功能，改善小鼠的神经元丢失并减少神经炎症并抑制神经胶质细胞激活在小鼠大脑中[6]。 Dihexa (PNB-0408)（10-6M-10-13M；30 分钟）保护侧线毛细胞免受氨基糖苷类的耳毒性。 Dihexa 不会改变氨基糖苷类药物进入毛细胞，而是通过 HGF 依赖性信号机制[7] 减弱细胞死亡。 Dihexa (PNB-0408)（2-4mg/kg；b.wt.；16 周）有望成为辅助疗法的候选药物，以促进手术神经修复后的肢体功能恢复，并对周围神经损伤和肢体移植有影响 [8].
| Cell experiment [1]: | |
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Cell lines |
Human embryonic kidney (HEK)-293 cells |
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Preparation Method |
Cells were seeded in six-well tissue culture plates. The cells were serum-deprived for 24 hours prior to the treatment to reduce the basal levels of phospho-Met. Following serum starvation, cocktails composed of vehicle and HGF with/without Dihexa (PNB-0408) or Nle1 -AngIV were prepared and preincubated for 30 minutes at room temperature. The cocktail was then added to the cells for 10 minutes to stimulate the Met receptor activation. Cells were harvested using radio immunoprecipitation assay lysis buffer supplemented with phosphatase inhibitor cocktails 1 and 2. |
|
Reaction Conditions |
10-10 M and 10-12 M;30 minutes; room temperature |
|
Applications |
Dihexa (PNB-0408) at both concentrations(10-10 M and 10-12 M) markedly augmented the capacity of HGF to activate c-Met. |
| Animal experiment [2]: | |
|
Animal models |
Male (APP/PS1) mice and wild-type (C57) mice |
|
Preparation Method |
The experiment was divided into two parts: Part 1, in which they were randomly divided into four groups: the WT group, the APP/PS1 group, the APP/PS1+ Dihexa (PNB-0408) (1.44 mg/kg) group, and the APP/PS1+ Dihexa (2.88 mg/kg) group, and Part 2, in which mice were divided into three groups: the APP/PS1 group, the Dihexa (2.88 mg/kg) group, and the Dihexa (2.88 mg/kg) + wortmannin group. Dihexa and wortmannin were dissolved in 10% DMSO, 40% PEG300, 5% Tween-80, and 45% saline, and administered intragastrically to the APP/PS1 mice. The Dihexa was administered intraperitoneally to the APP/PS1 mice from six to nine months old. Additionally, 0.9% saline was administered to the WT group once daily for three months. |
|
Dosage form |
1.44/2.88 mg/kg, i.g., for 3 months; 1.44/2.88 mg/kg, i.p., for 5 days. |
|
Applications |
Dihexa (PNB-0408) restored AngIV decline in APP/PS1 mice, saved the cognitive function of mice, improved neuronal loss in mice and reduced neuroinflammation and inhibited glial activation in the mouse brain. |
|
References: [1]. Benoist CC, Kawas LH, et,al.The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-met system. J Pharmacol Exp Ther. 2014 Nov;351(2):390-402. doi: 10.1124/jpet.114.218735. Epub 2014 Sep 3. PMID: 25187433; PMCID: PMC4201273. |
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| Cas No. | 1401708-83-5 | SDF | |
| 别名 | 益智二肽 | ||
| Canonical SMILES | OC1=CC=C(C[C@H](NC(CCCCC)=O)C(N[C@H](C(NCCCCCC(N)=O)=O)[C@@H](C)CC)=O)C=C1 | ||
| 分子式 | C27H44N4O5 | 分子量 | 504.66 |
| 溶解度 | DMSO : ≥ 30 mg/mL (59.45 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.9815 mL | 9.9077 mL | 19.8153 mL |
| 5 mM | 0.3963 mL | 1.9815 mL | 3.9631 mL |
| 10 mM | 0.1982 mL | 0.9908 mL | 1.9815 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Quality Control & SDS
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- Purity: >98.00%
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