Nalfurafine

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]。