nature

当前位置: Nature » 生物医学 » 正文

Nature:专治疼痛的订制阿片类药物

摘要 : 吗啡和来自罂粟的其它生物碱属于μ阿片受体激动剂,几百年来一直被用于治疗疼痛。

 吗啡和来自罂粟的其它生物碱属于μ阿片受体激动剂,几百年来一直被用于治疗疼痛。作者使用计算方法,将300多万种小分子与μ阿片受体对接。通过对最具潜力的结构的基于结构优化,研究者发现了一种强力激动剂PZM21,它对μ阿片受体具有超常的亚型选择性。在小鼠中,PZM21造成了显著的痛觉缺失,而在μ阿片受体敲除动物中完全不存在这种情况。这个小分子似乎降低了疼痛感知,但没有明显改变反射行为,而且对呼吸影响很小。

原文链接:

Structure-based discovery of opioid analgesics with reduced side effects

原文摘要:

Morphine is an alkaloid from the opium poppy used to treat pain. The potentially lethal side effects of morphine and related opioids—which include fatal respiratory depression—are thought to be mediated by μ-opioid-receptor (μOR) signalling through the β-arrestin pathway or by actions at other receptors. Conversely, G-protein μOR signalling is thought to confer analgesia. Here we computationally dock over 3 million molecules against the μOR structure and identify new scaffolds unrelated to known opioids. Structure-based optimization yields PZM21—a potent Gi activator with exceptional selectivity for μOR and minimal β-arrestin-2 recruitment. Unlike morphine, PZM21 is more efficacious for the affective component of analgesia versus the reflexive component and is devoid of both respiratory depression and morphine-like reinforcing activity in mice at equi-analgesic doses. PZM21 thus serves as both a probe to disentangle μOR signalling and a therapeutic lead that is devoid of many of the side effects of current opioids.

来源: Nature 浏览次数:1

热门文章TOP

RSS订阅 - 填写您的邮件地址,订阅我们的精彩内容: - 网站地图
网站联系电话:020-87540820 备案号:粤ICP备11050685号-8 增值电信业务经营许可证:粤B2-20120479
©2011-2015 生物帮 All rights reserved.