kappa opioid receptor (KOR)

Difelikefalin (CR-845; FE-202845) 不会穿透血脑屏障。 Difelikefalin 不与 mu 阿片受体或除 KOR 以外的任何其他受体结合[1]。

Absorption, Distribution and Excretion
Defecalin is administered via intravenous bolus injection with each hemodialysis session—therefore, the bioavailability of each dose is almost 100%. After intravenous injection, approximately 11% of the dose is excreted in the urine, 59% in the feces, and 20% in the dialysate. The mean volume of distribution of defecalin is approximately 238 mL/kg. A single hemodialysis cycle can reduce defecalin plasma concentration by 70-80%, and drug residues are undetectable after two cycles. Metabolism/Metabolites Defecalin is hardly metabolized and is not a substrate for cytochrome P450 enzymes. Biological Half-Life Before dialysis, the half-life of metformin in hemodialysis patients is 23 to 31 hours.

Protein Binding
Difelikefalin is approximately 23-28% bound to proteins in plasma, although it is unclear which specific proteins it binds to.

[1]. Randomized Controlled Trial of Difelikefalin for Chronic Pruritus in Hemodialysis Patients. Kidney Int Rep. 2020 Jan 28;5(5):600-610.

[2]. A Phase 3 Trial of Difelikefalin in Hemodialysis Patients With Pruritus. N Engl J Med. 2020 Jan 16;382(3):222-232.

Defecafalin (CR845) is a κ-opioid receptor (KOR) agonist used to treat pruritus secondary to chronic kidney disease (CKD). The association between KOR and pruritus was first discovered in 1984. Further research showed that the endogenous KOR agonist dynorphin could suppress pruritus at the spinal cord level, and that in mouse models, administration of KOR antagonists could induce scratching behavior. These findings prompted investigations into KOR agonists as a potential treatment for patients with pruritus. CKD-related pruritus (also known as uremic pruritus) affects 50-60% of dialysis patients and 25% of non-dialysis CKD patients. The clinical burden of uremic pruritus on these patients is increasingly recognized, as it leads to significantly reduced quality of life, poor prognosis, and even death. Treatment options are limited—due to the lack of FDA-approved therapies, off-label use [gabapentin] is the most well-supported and widely used treatment. Definalifarin was approved by the FDA in August 2021 (brand name Korsuva), becoming the first FDA-approved therapy for the treatment of pruritus associated with uremic syndrome in patients with chronic kidney disease. Definalifarin was subsequently approved by the EMA in April 2022 for the same indication. Definalifarin is a κ-opioid receptor agonist. Its mechanism of action is as an opioid κ-receptor agonist. See also: Definalifarin acetate (active ingredient).

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Drug Indications
Definalifarin is indicated for the treatment of moderate to severe pruritus associated with chronic kidney disease (CKD-aP; uremic pruritus) in adults undergoing hemodialysis.
FDA Label
Korsuva is indicated for the treatment of moderate to severe pruritus in adults with chronic kidney disease undergoing hemodialysis (see Section 5.1).
Treatment of Chronic Kidney Disease-Related Pruritus
Mechanism of Action

Defenfalin is a synthetic peptide and an agonist of the κ-opioid receptor (KOR), which has long been known to be associated with pruritus (and also plays a role in addiction). Endogenous κ-opioid receptor agonists (called dynorphins) have a neuroinhibitory effect on pruritus sensation at the spinal cord level, and mouse models have demonstrated their antipruritic activity in treating pruritus induced by various pruritogens. Although the specific mechanism is not fully elucidated, the use of κ-opioid receptor agonists (such as defenfalin) has proven to be an effective way to inhibit scratching and improve the quality of life for patients with uremic pruritus.
Pharmacodynamics

Defenfalin is used to treat hemodialysis patients with chronic kidney disease (CKD) to prevent and treat pruritus, a common CKD symptom. It is administered via intravenous bolus at the end of each hemodialysis session. Because defecallifalin acts on opioid receptors, it can cause dizziness, drowsiness, and other central nervous system depressant effects, thereby impairing mental or physical abilities—therefore, patients should be advised to avoid operating dangerous machinery until they understand the effects of defecallifalin on them.

C36H53N7O6

679.86

679.406

C, 63.60; H, 7.86; N, 14.42; O, 14.12

1024828-77-0

413256-25-2 (1HCl); 1024829-44-4 (acetate); 1024828-77-0; 2711717-77-8 (3HCl); 2742623-88-5 (TFA)

24794466

White to off-white solid powder

4.044

222.97

7

9

18

49

1080

4

O([H])C(C1(C([H])([H])C([H])([H])N(C([C@@]([H])(C([H])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H])N([H])C([C@@]([H])(C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H])N([H])C([C@@]([H])(C([H])([H])C2C([H])=C([H])C([H])=C([H])C=2[H])N([H])C([C@@]([H])(C([H])([H])C2C([H])=C([H])C([H])=C([H])C=2[H])N([H])[H])=O)=O)=O)=O)C([H])([H])C1([H])[H])N([H])[H])=O

FWMNVWWHGCHHJJ-SKKKGAJSSA-N

InChI=1S/C36H53N7O6/c1-24(2)21-29(32(45)40-28(15-9-10-18-37)34(47)43-19-16-36(39,17-20-43)35(48)49)42-33(46)30(23-26-13-7-4-8-14-26)41-31(44)27(38)22-25-11-5-3-6-12-25/h3-8,11-14,24,27-30H,9-10,15-23,37-39H2,1-2H3,(H,40,45)(H,41,44)(H,42,46)(H,48,49)/t27-,28-,29-,30-/m1/s1

4-amino-1-[(2R)-6-amino-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid

MR-13A9; CR-845; MR-13A-9; MR13A9; CR845; MR13A-9; trade name Korsuva

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ~100 mg/mL (~147.1 mM)
H2O: ≥ 100 mg/mL (~147.1 mM)

配方 1 中的溶解度: ≥ 2.5 mg/mL (3.68 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (3.68 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (3.68 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。