美国斯坦福大学医学院Kobilka, Brian K.团队报道了一种与纳洛酮协同作用的μ-阿片受体调节剂。相关研究成果发表在2024年7月3日出版的《自然》。

μ-阿片受体（μOR）是公认的镇痛靶点，但传统的阿片受体激动剂会引起严重的不良反应，尤其是成瘾和呼吸抑制。这些因素导致了芬太尼2（一种强效合成阿片类药物）导致的当前阿片类过量使用。μOR阴性变构调节剂（NAMs）可能是预防阿片类药物过量死亡的有用工具，但有前景的化学支架仍然难以捉摸。

该文中，研究人员筛选了一个针对无活性μOR的大型DNA编码化学文库，用活性G蛋白和激动剂结合受体进行反筛选，以“引导”命中构象选择性调节剂。研究发现了一种对无活性μOR具有高选择性富集的NAM化合物，该化合物增强了关键的阿片类药物过量逆转分子纳洛酮的亲和力。NAM与纳洛酮协同作用，有效阻断阿片类激动剂信号传导。

研究人员使用低温电子显微镜证明NAM通过与纳洛酮直接接触结合细胞外前庭上的一个位点来实现这一作用，同时稳定第二和第七跨膜螺旋的细胞外部分的不同非活性构象。NAM以治疗所需的方式改变正构配体动力学，并与低剂量纳洛酮协同作用，有效抑制体内吗啡诱导和芬太尼诱导的各种行为效应，同时最大限度地减少戒断行为。

研究结果为μOR的负变构调节机制提供了详细的结构见解，并证明了如何在体内利用这一点。

附：英文原文

Title: A μ-opioid receptor modulator that works cooperatively with naloxone

Author: OBrien, Evan S., Rangari, Vipin Ashok, El Daibani, Amal, Eans, Shainnel O., Hammond, Haylee R., White, Elizabeth, Wang, Haoqing, Shiimura, Yuki, Krishna Kumar, Kaavya, Jiang, Qianru, Appourchaux, Kevin, Huang, Weijiao, Zhang, Chensong, Kennedy, Brandon J., Mathiesen, Jesper M., Che, Tao, McLaughlin, Jay P., Majumdar, Susruta, Kobilka, Brian K.

Issue&Volume: 2024-07-03

Abstract: The μ-opioid receptor (μOR) is a well-established target for analgesia1, yet conventional opioid receptor agonists cause serious adverse effects, notably addiction and respiratory depression. These factors have contributed to the current opioid overdose epidemic driven by fentanyl2, a highly potent synthetic opioid. μOR negative allosteric modulators (NAMs) may serve as useful tools in preventing opioid overdose deaths, but promising chemical scaffolds remain elusive. Here we screened a large DNA-encoded chemical library against inactive μOR, counter-screening with active, G-protein and agonist-bound receptor to ‘steer’ hits towards conformationally selective modulators. We discovered a NAM compound with high and selective enrichment to inactive μOR that enhances the affinity of the key opioid overdose reversal molecule, naloxone. The NAM works cooperatively with naloxone to potently block opioid agonist signalling. Using cryogenic electron microscopy, we demonstrate that the NAM accomplishes this effect by binding a site on the extracellular vestibule in direct contact with naloxone while stabilizing a distinct inactive conformation of the extracellular portions of the second and seventh transmembrane helices. The NAM alters orthosteric ligand kinetics in therapeutically desirable ways and works cooperatively with low doses of naloxone to effectively inhibit various morphine-induced and fentanyl-induced behavioural effects in vivo while minimizing withdrawal behaviours. Our results provide detailed structural insights into the mechanism of negative allosteric modulation of the μOR and demonstrate how this can be exploited in vivo.

DOI: 10.1038/s41586-024-07587-7

Source: https://www.nature.com/articles/s41586-024-07587-7