Synthesis of unnatural morphinan compounds to induce itch-like behaviors in mice: Towards the development of MRGPRX2 selective ligands
Synthesis of unnatural morphinan compounds to induce itch-like behaviors in mice: Towards the development of MRGPRX2 selective ligands
复制标题
合成非天然吗啡喃化合物诱导小鼠瘙痒样行为：迈向 MRGPRX2 选择性配体的开发
DOI：
10.1016/j.bmcl.2021.128485
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Nagase Hiroshi
中科院分区：
文献类型：
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作者：
Iio Keita;Kutsumura Noriki;Nagumo Yasuyuki;Saitoh Tsuyoshi;Tokuda Akihisa;Hashimoto Kao;Yamamoto Naoshi;Kise Ryoji;Inoue Asuka;Mizoguchi Hirokazu;Nagase Hiroshi
MAS相关G蛋白偶联受体X2（MRGPRX 2）介导神经元中的瘙痒反应，并参与特应性皮炎（AD）相关炎症和瘙痒。有效的和MRGPRX 2选择性配体是必不可少的了解受体的详细功能，并开发新的治疗药物，其相关疾病。据报道，δ-阿片受体（DOR）选择性配体（-）-TAN-67（1）的对映体（+）-TAN-67（1）可激活MRGPRX 2，尽管（+）-1也与DOR相互作用，这使研究者无法探究MRGPRX 2的功能。在这里，我们已经成功地开发了一种新的非天然吗啡喃化合物（+）-2通过基于（+）-1的结构的转化，其去除了DOR结合亲和力。（+）-2a在体外实验中激活人MRGPRX 2和小鼠直系同源物Mrgprb 2，并在小鼠中诱导瘙痒样行为，其程度与（+）-1相同。通过给予三肽QWF（一种MRGPRX 2/Mrgprb 2拮抗剂）或抗瘙痒药物纳呋拉芬，可抑制小鼠中（+）-2a诱导的瘙痒反应。总之，（+）-2作为一个有用的工具来阐明MRGPRX 2及其小鼠直向同源物Mrgprb 2的瘙痒相关功能/作用。
Mas-related G protein-coupled receptor X2 (MRGPRX2) mediates the itch response in neurons and is involved in atopic dermatitis (AD)-associated inflammation and itch. Potent and MRGPRX2-selective ligands are essential to an understanding of the detailed function of the receptor and to develop new therapeutic agents for its related diseases. (+)-TAN-67 (1), the enantiomer of the δ-opioid receptor (DOR) selective ligand (–)-TAN-67 (1), has been reported to activate MRGPRX2, although (+)-1also interacts with DOR, which prevents investigators from interrogating the function of MRGPRX2. Here, we have succeeded in developing a novel unnatural morphinan compound (+)-2aby a transformation based on the structure of (+)-1, which removes the DOR binding affinity. (+)-2aactivated both human MRGPRX2 and the mouse orthologue Mrgprb2 inin vitroexperiments and induced itch-like behaviors in mice to the same extent as (+)-1. The (+)-2a-induced itch response in mice was suppressed by administration of the tripeptide QWF, an MRGPRX2/Mrgprb2 antagonist, or the antipruritic drug nalfurafine. Together, (+)-2aserves as a useful tool to elucidate the itch-related function/action of MRGPRX2 and its mouse orthologue Mrgprb2.