Nalfurafine
(Synonyms: 纳呋拉啡; TRK-820) 目录号 : GC44312An Analytical Reference Standard
Cas No.:152657-84-6
Sample solution is provided at 25 µL, 10mM.
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Nalfurafine is a κ-opioid receptor (KOR) agonist (EC50 = 0.05 nM for human receptors expressed in CHO cell membranes). [1] It is selective for κ-opioid over μ- and δ-opioid receptors (EC50s = 0.72 and 74.1 nM, respectively). Nalfurafine (≥30 μg/kg) reduces scratching behavior induced by chloroquine in mice, as well as locomotor activity when administered at a dose of 100 μg/kg.[2] In rats, nalfurafine (≥0.01 mg/kg) reduces intracranial self-stimulation, lactic acid-induced stretching behavior, and scratching behavior induced by intradermal administration of serotonin . [3] Nalfurafine is also an orexin 1 receptor (OX1R) antagonist (Ki = 250 nM).[4]
Reference:
[1]. Watanabe, Y., Kitazawa, S., Fujii, H., et al. Design, synthesis, and structure-activity relationship of novel opioid κ receptor selective agonists: α-Iminoamide derivatives with an azabicyclo[2.2.2]octene skeleton. Bioorg. Med. Chem. Lett 24(21), 4980-4983 (2014).
[2]. Tarrasón, G., Carcasona, C., Eichhorn, P., et al. Characterization of the chloroquine-induced mouse model of pruritus using an automated behavioural system. Exp. Dermatol. 26(11), 1105-1111 (2017).
[3]. Lazenka, M.L., Moerke, M.J., Townsend, E.A., et al. Dissociable effects of the kappa opioid receptor agonist nalfurafine on pain/itch-stimulated and pain/itch-depressed behaviors in male rats. Psychopharmacol. (Berl). 235(1), 203-213 (2018).
[4]. Nagase, H., Yamamoto, N., Yata, M., et al. Design and synthesis of potent and highly selective orexin 1 receptor antagonists with a morphinan skeleton and their pharmacologies. J. Med. Chem. 60(3), 1018-1040 (2017).
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 |
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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 |
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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.