Nalfurafine
(Synonyms: 纳呋拉啡; TRK-820) 目录号 : GC44312
纳呋法芬（TRK-820）是一种强效选择性口服活性G蛋白偏向kappa阿片受体（KOR）激动剂。
Cas No.:152657-84-6
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >95.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
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Cell experiment [1]: |
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Cell lines |
CHO cell lines |
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Preparation method |
Cells (5000/well) expressing the cloned μ-, δ- or κ-opioid receptors were seeded in 96-well plates overnight and then exposed to Nalfurafine(TRK-820) at 0.01 nM-1mM. |
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Reaction Conditions |
0.01 nM-1mM |
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Applications |
The IC50 value of Nalfurafine(TRK-820) was 0.15 ± 0.08nM. TRK-820 inhibited forskolin-stimulated intracellular cAMP accumulation in a concentration-dependent manner in CHO/KOPR. |
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Animal experiment [2]: |
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Animal models |
Male C57BL/6 mice (weighing 22–27 g) |
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Preparation method |
Mice received intrathecal injections of one of the following drugs: morphine (0.1–1.0 nmol), the selective KOR agonist Nalfurafine(TRK-820)100 pmol, the combination of morphine 0.3 nmol + Nalfurafine(TRK-820)(10–100 pmol), and 5 μL of saline. |
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Dosage form |
100 pmol intrathecal injection |
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Applications |
Nalfurafine(TRK-820) exert antipruritic effects on intrathecal morphine–induced itch without affecting sedation. The combination of intrathecal morphine and Nalfurafine(TRK-820) produces more potent antinociceptive effects against a thermal stimulus compared with morphine alone. |
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References: [1] Seki T , Awamura S , Kimura C ,et al.Pharmacological properties of TRK-820 on cloned μ-, δ- and κ-opioid receptors and nociceptin receptor[J].European Journal of Pharmacology, 1999, 376(1-2):159. [2] Sakakihara M, Imamachi N, Saito Y. Effects of intrathecal κ-opioid receptor agonist on morphine-induced itch and antinociception in mice[J]. Regional Anesthesia & Pain Medicine, 2016, 41(1): 69-74. |
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Nalfurafine (TRK-820) is a potent and selective, orally active G protein-biased kappa opioid receptor (KOR) agonist with high translational potential. Nalfurafine enhances the biological effects of μ Opioid Receptor (MOR)-targeting analgesics, and it also has potential for research related to uremic pruritus treatment[1].
In vitro, Nalfurafine (TRK-820) of agonistic activity was evaluated by the inhibitory effect it had on forskolin 10 μM–stimulated intracellular cAMP accumulation. Nalfurafine inhibited forskolin-stimulated intracellular cAMP accumulation in a concentration-dependent manner in CHO/KOPR. The IC50 value of Nalfurafine was 0.15 ± 0.08nM, which was about 100 fold smaller than that of U69593, a κ-opioid receptor-selective agonist (IC50=16 ± 6 nM)[2].
In vivo, Nalfurafine (TRK-820) was topically administered to the naïve or neovascularized cornea once or twice a day (0.1 µg/2 μL/eye). Nalfurafine twice daily significantly suppressed Choroidal Neovascularization (CNV) and lymphangiogenesis, as well as reduced the mRNA levels of angiogenic and pro-inflammatory factors in the neovascularized corneas. Moreover, Nalfurafine e administration twice daily reduced the numbers of infiltrating leukocytes, neutrophils, macrophages, and interferon-γ-producing CD4+ T cells in the neovascularized corneas[3]. Nalbuphine (subcutaneous injection, 4μg/kg) on acetic acid-induced abdominal wall contraction increases in a dose-dependent manner. The inhibitory effect on abdominal wall contraction reaches its peak 30 minutes after injection and gradually decreases after 4 hours, returning to the level before injection[4].
Inflammatory mediators activate G proteins that upregulate cyclic adenosine monophosphate (cAMP) generation, which in turn activates the protein kinase A pathway for vascular endothelial growth factor (VEGF) production, whereas Nalfurafine activation suppresses VEGF production by promoting Gαi/o inhibition of adenylyl cyclase, which decreases cAMP levels and attenuates protein kinase A activation[3].
Fig 1 Mechanism of the effect of the Nalfurafine agonist on local neovascularization
References:
[1] Kaski SW, et al. Preclinical Testing of Nalfurafine as an Opioid-sparing Adjuvant that Potentiates Analgesia by the Mu Opioid Receptor-targeting Agonist Morphine.J Pharmacol Exp Ther. 2019 Nov;371(2):487-499.
[2] Seki T , Awamura S , Kimura C ,et al.Pharmacological properties of TRK-820 on cloned μ-, δ- and κ-opioid receptors and nociceptin receptor[J].European Journal of Pharmacology, 1999, 376(1-2):159.
[3] Shokirova H, Inomata T, Saitoh T, et al. Topical administration of the kappa opioid receptor agonist nalfurafine suppresses corneal neovascularization and inflammation[J]. Scientific Reports, 2021, 11(1): 8647.
[4] Endoh T, et al. Potent antinociceptive effects of TRK-820, a novel kappa-opioid receptor agonist.Life Sci. 1999;65(16):1685-94.
纳呋法芬（TRK-820）是一种强效选择性口服活性G蛋白偏向kappa阿片受体（KOR）激动剂，具有较高的转化潜力。纳呋法芬（TRK-820）增强了μ 阿片受体（MOR）靶向止痛药物的生物效应，同时也具有研究尿毒性瘙痒治疗相关的潜力[1]。
体外实验中，TRK-820 的激动活性是通过其对forskolin 10µM刺激下的细胞内cAMP积累的抑制作用进行评估。TRK-820在CHO/KOPR中以浓度依赖的方式抑制了forskolin刺激的细胞内cAMP积累。TRK-820的IC50值为0.15 ± 0.08nM，比k-阿片受体选择性激动剂U69593的IC50值（16 ± 6 nM）小约100倍[2]。
体内实验中，纳呋法芬局部施用于天然或新生血管化的角膜，一天一次或一天两次（0.1µg/2μL/眼）。每天两次纳呋法芬显著抑制脉络膜新生血管（CNV）和淋巴管生成，同时减少新生血管化角膜中血管生成和促炎因子的mRNA水平。此外，每天两次纳呋法芬降低了新生血管化角膜中浸润的白细胞、中性粒细胞、巨噬细胞和产生干扰素-γ的CD4+T细胞数量[3]。对乙酸诱导的腹壁收缩，纳呋法芬（皮下注射，4μg/kg）剂量依赖性增加。腹壁收缩的抑制作用在注射后30分钟达到峰值，4小时后逐渐减弱，回归注射前水平[4]。
炎症介质激活促进G蛋白上调环腺苷单磷酸（cAMP）生成，而后激活蛋白激酶A通路促进血管内皮生长因子（VEGF）的产生，而纳尔麦啶的激活通过促进Gαi/o抑制腺苷酸环化酶抑制VEGF的生成，降低cAMP水平并减弱蛋白激酶A的激活[3]。
| Cas No. | 152657-84-6 | SDF | |
| 别名 | 纳呋拉啡; TRK-820 | ||
| 化学名 | (2E)-N-[(5α,6β)-17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxymorphinan-6-yl]-3-(3-furanyl)-N-methyl-2-propenamide | ||
| Canonical SMILES | O[C@]12[C@]3(CCN(CC4CC4)[C@@H]2C5)[C@](OC6=C3C5=CC=C6O)([H])[C@H](N(C)C(/C=C/C7=COC=C7)=O)CC1 | ||
| 分子式 | C28H32N2O5 | 分子量 | 476.6 |
| 溶解度 | 33mg/ml in DMSO | 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 | 2.0982 mL | 10.491 mL | 20.982 mL |
| 5 mM | 0.4196 mL | 2.0982 mL | 4.1964 mL |
| 10 mM | 0.2098 mL | 1.0491 mL | 2.0982 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。
Nalfurafine hydrochloride to treat pruritus: a review
Clin Cosmet Investig Dermatol 2015 May 11;8:249-55.PMID:26005355DOI:10.2147/CCID.S55942.
Uremic pruritus has a great negative influence on quality of life in hemodialysis (HD) patients and, importantly, negatively affects mortality risk. Recently, Nalfurafine hydrochloride, an opioid κ-selective agonist, has been officially approved for resistant pruritus in HD patients on the basis of a well-evidenced clinical trial in Japan. From clinical observation, it has been suggested that the upper neuron system plays a role in its pathogenesis. According to previous experimental results, using mice injected with opioids, dynorphin suppresses itch through binding κ-opioid receptors, suggesting that κ-opioid opioid receptor agonists act as potential therapeutic reagents for pruritus in HD patients. In Japan, a large-scale placebo-controlled study was performed to examine the efficacy and safety of oral Nalfurafine hydrochloride for intractable pruritus in 337 HD patients. Two daily doses of 2.5 or 5 μg Nalfurafine or placebo were orally administered for 2 weeks, and clinical responses were analyzed. The results showed that the mean decrease in the visual analog scale for pruritus from baseline was 22 mm in the 5 μg Nalfurafine hydrochloride group (n=114) and 23 mm in the 2.5 μg group (n=112). These reductions were statistically significant compared with 13 mm, which is the mean decrease of visual analog scale in the placebo group (n=111), demonstrating that Nalfurafine is an effective and safe drug for uremic pruritus in HD patients. Moreover, another open-label trial (n=145) examining the long-term effect of 5 μg oral Nalfurafine revealed the maintenance of the antipruritic effect of Nalfurafine for 52 weeks. In addition, on the basis of recent data showing κ-opioid receptor expression in the epidermis of atopic dermatitis and psoriasis, Nalfurafine hydrochloride also can be potentially used for these two skin diseases.
Nalfurafine hydrochloride for the treatment of pruritus
Expert Opin Pharmacother 2012 Jul;13(10):1507-13.PMID:22663138DOI:10.1517/14656566.2012.693164.
Introduction: Severe pruritus associated with end-stage renal disease is a particularly troublesome complication, because no effective treatment has been established. However, based on the findings of a recent randomized controlled trial, Nalfurafine hydrochloride was officially approved in Japan for the treatment of resistant pruritus in hemodialysis patients. Areas covered: This review is based upon a PubMed search and personal experience with Nalfurafine hydrochloride. The pharmacokinetics and pharmacodynamics of Nalfurafine hydrochloride are reviewed and its efficiency and potential adverse effects are discussed, mainly based on the findings of randomized controlled trials. Expert opinion: A recent long-term open trial showed that the effect of Nalfurafine hydrochloride was enhanced by continuous, long-term administration. It will be of future interest to investigate its effect on excoriations, lichen simplex, prurigo nodularis and acquired perforating dermatosis (all caused by uremic pruritus), because it targets both the skin and the central nervous system. In clinical practice, it should be kept in mind that basic skin care with emollients and other topical drugs is essential for stopping the itch-scratch cycle, and the resultant skin barrier dysfunction.
Preclinical Studies on Nalfurafine (TRK-820), a Clinically Used KOR Agonist
Handb Exp Pharmacol 2022;271:137-162.PMID:33834276DOI:10.1007/164_2021_443.
Nalfurafine has been used clinically in Japan for treatment of itch in kidney dialysis patients and in patients with chronic liver diseases. A one-year post-marketing study showed Nalfurafine to be safe and efficacious without producing side effects of typical KOR agonists such as anhedonia and psychotomimesis. In this chapter, we summarize in vitro characterization and in vivo preclinical studies on Nalfurafine. In vitro, Nalfurafine is a highly potent and moderately selective KOR full agonist; however, whether it is a biased KOR agonist is a matter of debate. In animals, Nalfurafine produced anti-pruritic effects in a dose range lower than that caused side effects, including conditioned place aversion (CPA), hypolocomotion, motor incoordination, consistent with the human data. In addition, Nalfurafine showed antinociceptive effects in several pain models at doses that did not cause the side effects mentioned above. It appears to be effective against inflammatory pain and mechanical pain, but less so against thermal pain, particularly high-intensity thermal pain. U50,488H and Nalfurafine differentially modulated several signaling pathways in a brain region-specific manners. Notably, U50,488H, but not Nalfurafine, activated the mTOR pathway, which contributed to U50,488H-induced CPA. Because of its lack of side effects associated with typical KOR agonists, Nalfurafine has been investigated as a combination therapy with an MOR ligand for pain treatment and for its effects on opioid use disorder and alcohol use disorder, and results indicate potential usefulness for these indications. Thus, although in vitro data regarding uniqueness of Nalfurafine in terms of signaling at the KOR are somewhat equivocal, in vivo results support the assertion that Nalfurafine is an atypical KOR agonist with a significantly improved side-effect profile relative to typical KOR agonists.
Nalfurafine, a G-Protein-Biased KOR (Kappa Opioid Receptor) Agonist, Enhances the Diuretic Response and Limits Electrolyte Losses to Standard-of-Care Diuretics
Hypertension 2022 Feb;79(2):379-390.PMID:34852633DOI:10.1161/HYPERTENSIONAHA.121.18503.
Nalfurafine is a G-protein-biased KOR (kappa opioid receptor) agonist that produces analgesia and lacks central nervous system adverse effects. Here, we examined the cardiovascular and renal responses to intravenous and oral Nalfurafine alone and in combination with furosemide, hydrochlorothiazide, or amiloride. We hypothesized that Nalfurafine, given its distinct mechanism of vasopressin inhibition, would increase urine output to these diuretics and limit electrolyte loss. Following catheterization, conscious Sprague-Dawley rats received an isotonic saline infusion and were then administered an intravenous bolus of Nalfurafine, a diuretic, or a combination. Mean arterial pressure, heart rate, and urine output were recorded for 90 minutes. In another study, rats were placed in metabolic cages and administered drug in an oral volume load. Hourly urine samples were then collected for 5 hours. Intravenous and oral Nalfurafine produced a marked diuresis, antinatriuresis, antikaliuresis, and a decrease in mean arterial pressure. Compared with diuretic treatment alone, intravenous coadministration with Nalfurafine significantly increased urine output to furosemide and hydrochlorothiazide and decreased sodium and potassium excretion. Notably, mean arterial pressure was reduced with Nalfurafine/diuretic combination therapy compared to diuretics alone. Similarly, oral coadministration of Nalfurafine significantly increased urine output to hydrochlorothiazide and decreased sodium and potassium excretion, whereas combination with furosemide only limited the amount of sodium excreted. Further, both intravenous and oral coadministration of Nalfurafine enhanced the diuresis to amiloride and decreased sodium excretion. Together, these findings demonstrate that Nalfurafine enhances the diuresis to standard-of-care diuretics without causing an excessive loss of electrolytes, offering a new approach to treat several cardiovascular conditions.
Nalfurafine hydrochloride: a new drug for the treatment of uremic pruritus in hemodialysis patients
Drugs Today (Barc) 2009 May;45(5):323-9.PMID:19584962DOI:10.1358/dot.2009.45.5.1362067.
Uremic pruritus in hemodialysis patients is intractable and no effective treatments have been established yet. Although the precise mechanism of the pruritus is still unclear, accumulating evidence suggests that activation of the micro-opioid receptors may induce pruritus in hemodialysis patients. On the other hand, activation of kappa-opioid receptors is known to control or inhibit the signals activated through micro-opioid receptors; therefore, it was expected that kappa-opioid receptor agonists would be able to reduce pruritus in patients undergoing hemodialysis. Nalfurafine hydrochloride is a novel derivative of the opioid receptor antagonist naltrexone. Nalfurafine hydrochloride is a selective kappa-opioid receptor agonist and has a potent antipruritic effect on various types of pruritus through central kappa-opioid receptor activation in non-clinical pharmacological studies. Moreover, clinical studies have demonstrated that Nalfurafine hydrochloride possesses efficacy and safety in hemodialysis patients with uremic pruritus. In this review, we provide a detailed description of the activity of Nalfurafine hydrochloride using published data of in vitro, in vivo nonclinical pharmacological and clinical studies in hemodialysis patients with uremic pruritus.