Preclinical Studies on Nalfurafine (TRK-820), a Clinically Used KOR Agonist.
Preclinical Studies on Nalfurafine (TRK-820), a Clinically Used KOR Agonist.
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DOI：
10.1007/164_2021_443
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发表时间：
2022
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在日本，纳氟非林已被临床用于治疗肾透析患者和慢性肝病患者的瘙痒。一项为期一年的上市后研究表明，纳氟芬是安全有效的，不会产生典型的KOR激动剂副作用，如快感缺乏和精神错乱。在本章中，我们总结了纳氟芬的体外表征和体内临床前研究。在体外，纳氟萘芬是一种高效、中等选择性的KOR完全激动剂；然而，它是否是一种偏颇的KOR激动剂是一个有争议的问题。在动物实验中，纳氟萘芬在较低剂量范围内产生了抗瘙痒作用，其副作用包括条件性场所厌恶（CPA）、低运动、运动不协调，与人类数据一致。此外，在几种疼痛模型中，纳氟萘芬在没有引起上述副作用的剂量下显示出抗痛觉作用。它似乎对炎症性疼痛和机械性疼痛模型有效，但对热痛，特别是高强度热痛效果较差。u50,488和纳氟萘芬在脑区域特异性方式中差异调节了几种信号通路。值得注意的是，U50,488H而非纳氟萘芬激活了mTOR通路，这有助于U50,488H诱导的CPA。由于其缺乏与典型的KOR激动剂相关的副作用，研究人员已经研究了纳氟萘芬与MOR配体联合治疗疼痛以及对阿片类药物使用障碍和酒精使用障碍的影响，结果表明对这些适应症可能有用。因此，尽管关于纳氟芬在KOR信号传导方面的独特性的体外数据有些模棱两可，但体内结果支持纳氟芬是一种非典型的KOR激动剂，相对于典型的KOR激动剂，其副作用显著改善。
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 typical of 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 that 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 models, but less so against thermal pain, particularly high-intensity thermal pain. U50,488H and nalfurafine differentially modulated several signaling pathways in 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 prototypical KOR agonists.