Analgesics with no abuse liability are highly demanded in the market. KOR agonists have been proved to be strong analgesics without MOR agonist-related side effects, such as respiratory depression, tolerance, and dependence liability; however, activation of KOR in the central nervous system (CNS) may cause sedation and anxiety. It has been reported that peripheral KOR activation produces comparable bioactivity without CNS-related side effects. Herein, we designed and synthesized a novel tetrapeptide (SHR0687), which was shown to be a highly potent KOR agonist with excellent selectivity over other opioid receptors, such as MOR and DOR. In addition, SHR0687 displayed favorable PK profiles across species, as well as robust in vivo efficacy in a rat carrageenan-induced pain model. Notably, SHR0687 exhibited negligible blood–brain barrier penetration, which was meaningful in minimizing CNS-related side effects.

中文翻译：

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发现 SHR0687，一种高效且外周神经系统受限的 KOR 激动剂

市场上对无滥用责任的镇痛药的需求量很大。KOR 激动剂已被证明是强镇痛剂，没有 MOR 激动剂相关的副作用，如呼吸抑制、耐受性和依赖性；然而，中枢神经系统 (CNS) 中 KOR 的激活可能会导致镇静和焦虑。据报道，外周 KOR 激活产生相当的生物活性，而没有中枢神经系统相关的副作用。在此，我们设计并合成了一种新型四肽 (SHR0687)，该四肽被证明是一种高效的 KOR 激动剂，与其他阿片受体（如 MOR 和 DOR）相比具有出色的选择性。此外，SHR0687 显示出良好的跨物种 PK 特征，以及强大的体内在大鼠角叉菜胶诱导的疼痛模型中的功效。值得注意的是，SHR0687 的血脑屏障渗透性可以忽略不计，这对于减少 CNS 相关的副作用是有意义的。