Discovery of a pyrano[2,3-b]pyridine derivative YX-2102 as a cannabinoid receptor 2 agonist for alleviating lung fibrosis.
Discovery of a pyrano[2,3-b]pyridine derivative YX-2102 as a cannabinoid receptor 2 agonist for alleviating lung fibrosis.
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发现pyrano [2,3-B]吡啶衍生物YX-2102作为大麻素受体2激动剂，用于减轻肺纤维化。
DOI：
10.1186/s12967-022-03773-1
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发表时间：
2022-12-06
影响因子：
7.4
通讯作者：
Ouyang, Qin
中科院分区：
文献类型：
--
作者：
Liu, Tao;Gu, Jing;Yuan, Yi;Yang, Qunfang;Zheng, Peng-Fei;Shan, Changyu;Wang, Fangqin;Li, Hongwei;Xie, Xiang-Qun;Chen, Xiao-Hong;Ouyang, Qin
关键词：
大麻素2受体（CB2R）的药理调节是一种有前途的治疗肺纤维化（PF）的策略。因此，开发具有新型化学空间的CB2R选择性配体已成为研究热点。本工作旨在从内部文库中发现一种新的CB2R激动剂，并评估其对PF模型的治疗效果，并揭示其药理机制。使用虚拟筛选从新建立的内部文库中鉴定CB2R的候选配体。通过PF大鼠模型体内实验和细胞体外实验，探讨该先导化合物的治疗作用及其机制。鉴定出一种“天然产物样”吡喃[2,3-b]吡啶衍生物YX-2102与CB2R具有高亲和力。YX-2102腹腔注射可显著改善博来霉素（BLM）致PF大鼠模型的肺损伤、炎症和纤维化。一方面，YX-2102至少部分通过调节巨噬细胞极化抑制炎症反应，从而发挥保护作用。另一方面，YX-2102在体内可显著上调肺泡上皮细胞中CB2R的表达。其预处理通过CB2受体依赖途径抑制肺泡上皮-间质转化（EMT）和转化生长因子β -1 （TGF-β1）诱导的肺泡肺纤维化模型。进一步的研究表明Nrf2-Smad7通路可能参与了。这些发现表明，CB2R是PF治疗的潜在靶点，而YX-2102是一种有前景的CB2R激动剂，具有新的化学空间。在线版本包含补充材料，可在10.1186/s12967-022-03773-1获得。
Pharmacological modulation of cannabinoid 2 receptor (CB2R) is a promising therapeutic strategy for pulmonary fibrosis (PF). Thus, to develop CB2R selective ligands with new chemical space has attracted much research interests. This work aims to discover a novel CB2R agonist from an in-house library, and to evaluate its therapeutic effects on PF model, as well as to disclose the pharmacological mechanism. Virtual screening was used to identify the candidate ligand for CB2R from a newly established in-house library. Both in vivo experiments on PF rat model and in vitro experiments on cells were performed to investigate the therapeutic effects of the lead compound and underlying mechanism. A “natural product-like” pyrano[2,3-b]pyridine derivative, YX-2102 was identified that bound to CB2R with high affinity. Intraperitoneal YX-2102 injections significantly ameliorated lung injury, inflammation and fibrosis in a rat model of PF induced by bleomycin (BLM). On one hand, YX-2102 inhibited inflammatory response at least partially through modulating macrophages polarization thereby exerting protective effects. Whereas, on the other hand, YX-2102 significantly upregulated CB2R expression in alveolar epithelial cells in vivo. Its pretreatment inhibited lung alveolar epithelial-to-mesenchymal transition (EMT) in vitro and PF model induced by transforming growth factor beta-1 (TGF-β1) via a CB2 receptor-dependent pathway. Further studies suggested that the Nrf2-Smad7 pathway might be involved in. These findings suggest that CB2R is a potential target for PF treatment and YX-2102 is a promising CB2R agonist with new chemical space. The online version contains supplementary material available at 10.1186/s12967-022-03773-1.
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