BPR1M97, a dual mu opioid receptor/nociceptin-orphanin FQ peptide receptor agonist, produces potent antinociceptive effects with safer properties than morphine
BPR1M97, a dual mu opioid receptor/nociceptin-orphanin FQ peptide receptor agonist, produces potent antinociceptive effects with safer properties than morphine
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DOI：
10.1016/j.neuropharm.2019.107678
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发表时间：
2020-04-01
影响因子：
4.7
通讯作者：
Yeh, Shiu-Hwa
中科院分区：
文献类型：
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作者：
Chao, Po-Kuan;Chang, Hsiao-Fu;Yeh, Shiu-Hwa
设计一种副作用较少的止痛药用于剧烈疼痛治疗是一种尚未得到满足的需求。虽然传统的阿片类药物是最有效的止痛药，但它们也伴随着严重的不良反应，如呼吸抑制、便秘症状、耐受性、戒断和成瘾。我们认为BPR1M97是一种双MU阿片受体(MOP)/伤害素-孤儿FQ肽(NOP)受体全激动剂，并在多种动物模型上研究了BPR1M97的药理作用。BPR1M97的体外研究通过环磷酸腺苷的产生、p-arrestin、内化和膜电位的测定来评估。通过甩尾、夹尾巴、肺功能、心脏功能、丙酮滴注、von Frey头发、木炭粉、玻璃珠、运动活动、条件性位置偏爱(CPP)和纳洛酮沉淀试验对体内研究进行了表征。对于在表达MOP的细胞中测试的所有基于细胞的分析，BPR1M97都能激发出完整的激动剂特性。然而，它是一种偏向G蛋白的NOP激动剂。BPR1M97在皮下注射后10min起效更快，对癌性疼痛的镇痛效果优于吗啡。与吗啡不同，BPR1M97引起的呼吸、心血管和胃肠功能障碍较少。此外，BPR1M97降低了整体活动，减少了纳洛酮引起的戒断跳跃。因此，BPR1M97可以作为一种新型的小分子双受体激动剂，具有比吗啡更少的副作用。本文是《阿片类药物药理学新前景》特刊的一部分。
There is unmet need to design an analgesic with fewer side effects for severe pain management. Although traditional opioids are the most effective painkillers, they are accompanied by severe adverse responses, such as respiratory depression, constipation symptoms, tolerance, withdrawal, and addiction. We indicated BPR1M97 as a dual mu opioid receptor (MOP)/nociceptin-orphanin FQ peptide (NOP) receptor full agonist and investigated the pharmacology of BPR1M97 in multiple animal models. In vitro studies on BPR1M97 were assessed using cyclic-adenosine monophosphate production, p-arrestin, internalization, and membrane potential assays. In vivo studies were characterized using the tail-flick, tail-clip, lung functional, heart functional, acetone drop, von Frey hair, charcoal meal, glass bead, locomotor activity, conditioned place preference (CPP) and naloxone precipitation tests. BPR1M97 elicited full agonist properties for all cell-based assays tested in MOP-expressing cells. However, it acted as a G protein-biased agonist for NOP. BPR1M97 initiated faster antinociceptive effects at 10 min after subcutaneous injection and elicited better analgesia in cancer-induced pain than morphine. Unlike morphine, BPR1M97 caused less respiratory, cardiovascular, and gastrointestinal dysfunction. In addition, BPR1M97 decreased global activity and induced less withdrawal jumping precipitated by naloxone. Thus, BPR1M97 could serve as a novel small molecule dual receptor agonist for antinociception with fewer side effects than morphine.This article is part of the Special Issue entitled 'New Vistas in Opioid Pharmacology'.