强效且外周神经系统选择性κ阿片受体激动剂SHR0687的发现
Discovery of SHR0687, a Highly Potent and Peripheral Nervous System-Restricted KOR Agonist.
作者信息
Li Xin, Wan Hong, Dong Ping, Wang Bin, Zhang Lei, Hu Qiyue, Zhang Ting, Feng Jun, He Feng, Bai Chang, Zhang Lianshan, Tao Weikang
机构信息
Shanghai Hengrui Pharmaceutical CO., LTD., 279 Wenjing Road, Shanghai 200245, China.
Chengdu Suncadia Medicine CO., LTD., 88 South Keyuan Road, Chengdu, Si Chuan 610000, China.
出版信息
ACS Med Chem Lett. 2020 Sep 14;11(11):2151-2155. doi: 10.1021/acsmedchemlett.0c00287. eCollection 2020 Nov 12.
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 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.
市场对无滥用倾向的镇痛药有很高的需求。已证实κ阿片受体（KOR）激动剂是强效镇痛药，没有与μ阿片受体（MOR）激动剂相关的副作用，如呼吸抑制、耐受性和成瘾性；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，而没有与CNS相关的副作用。在此，我们设计并合成了一种新型四肽（SHR0687），它被证明是一种高效的KOR激动剂，对其他阿片受体，如MOR和δ阿片受体（DOR）具有优异的选择性。此外，SHR0687在各物种中显示出良好的药代动力学特征，以及在大鼠角叉菜胶诱导的疼痛模型中具有强大的疗效。值得注意的是，SHR0687表现出可忽略不计的血脑屏障穿透率，这对于将与CNS相关的副作用降至最低具有重要意义。
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