BACKGROUND AND PURPOSE The endocannabinoid system and PPARγ are important targets for the development of novel compounds against fibrotic diseases such as systemic sclerosis (SSc), also called scleroderma. The aim of this study was to characterize VCE-004.3, a novel cannabidiol derivative, and study its anti-inflammatory and anti-fibrotic activities. EXPERIMENTAL APPROACH The binding of VCE-004.3 to CB1 and CB2 receptors and PPARγ and its effect on their functional activities were studied in vitro and in silico. Anti-fibrotic effects of VCE-004.3 were investigated in NIH-3T3 fibroblasts and human dermal fibroblasts. To assess its anti-inflammatory and anti-fibrotic efficacy in vivo, we used two complementary models of bleomycin-induced fibrosis. Its effect on ERK1/2 phosphorylation induced by IgG from SSc patients and PDGF was also investigated. KEY RESULTS VCE-004.3 bound to and activated PPARγ and CB2 receptors and antagonized CB1 receptors. VCE-004.3 bound to an alternative site at the PPARγ ligand binding pocket. VCE-004.3 inhibited collagen gene transcription and synthesis and prevented TGFβ-induced fibroblast migration and differentiation to myofibroblasts. It prevented skin fibrosis, myofibroblast differentiation and ERK1/2 phosphorylation in bleomycin-induced skin fibrosis. Furthermore, it reduced mast cell degranulation, macrophage activation, T-lymphocyte infiltration, and the expression of inflammatory and profibrotic factors. Topical application of VCE-004.3 also alleviated skin fibrosis. Finally, VCE-004.3 inhibited PDGF-BB- and SSc IgG-induced ERK1/2 activation in fibroblasts. CONCLUSIONS AND IMPLICATIONS VCE-004.3 is a novel semisynthetic cannabidiol derivative that behaves as a dual PPARγ/CB2 agonist and CB1 receptor modulator that could be considered for the development of novel therapies against different forms of scleroderma.

中文翻译：

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VCE-004.3 是一种大麻二酚氨基醌衍生物，通过 PPARγ 和 CB2 受体依赖性途径防止博来霉素诱导的皮肤纤维化和炎症。


背景和目的 内源性大麻素系统和 PPARγ 是开发针对纤维化疾病的新型化合物的重要靶点，例如系统性硬化症 （SSc），也称为硬皮病。本研究的目的是表征新型大麻二酚衍生物 VCE-004.3，并研究其抗炎和抗纤维化活性。实验方法 在体外和计算机中研究了 VCE-004.3 与 CB1 和 CB2 受体以及 PPARγ 的结合及其对其功能活性的影响。研究了 VCE-004.3 在 NIH-3T3 成纤维细胞和人真皮成纤维细胞中的抗纤维化作用。为了评估其在体内的抗炎和抗纤维化功效，我们使用了博来霉素诱导的纤维化的两种互补模型。还研究了它对 SSc 患者 IgG 和 PDGF 诱导的 ERK1/2 磷酸化的影响。主要结果 VCE-004.3 结合并激活 PPARγ 和 CB2 受体以及拮抗 CB1 受体。VCE-004.3 结合到 PPARγ 配体结合口袋的替代位点。VCE-004.3 抑制胶原基因转录和合成，并阻止 TGFβ 诱导的成纤维细胞迁移和分化为肌成纤维细胞。它阻止了博来霉素诱导的皮肤纤维化、肌成纤维细胞分化和 ERK1/2 磷酸化。此外，它还减少了肥大细胞脱颗粒、巨噬细胞活化、T 淋巴细胞浸润以及炎症和促纤维化因子的表达。VCE-004.3 的局部应用也缓解了皮肤纤维化。最后，VCE-004.3 抑制 PDGF-BB 和 SSc IgG 诱导的成纤维细胞 ERK1/2 活化。结论和影响 VCE-004。3 是一种新型半合成大麻二酚衍生物，其行为类似于双重 PPARγ/CB2 激动剂和 CB1 受体调节剂，可考虑用于开发针对不同形式硬皮病的新疗法。