The CB2 receptor plays a crucial role in analgesia and anti-inflammation. To develop novel CB2 agonists with high efficacy and selectivity, a series of indole derivatives with N-ethyl morpholine moieties (compounds 1–56) were designed, synthesized and biologically evaluated. Compounds 1, 2, 3, 46 and 53 exhibited high CB2 receptor affinity at low nanomolar concentrations and good receptor selectivity (EC₅₀(CB1)/EC₅₀(CB2) greater than 1000). The most active compound, compound 2, was more potent than the standard drug GW405833 for in vitro agonistic action on the CB2 receptor. More importantly, in a rat model for CFA-induced inflammatory hyperalgesia, compound 2 had a potent anti-inflammatory pain effect within 12 hours after administration. At the 1 h time point, compound 2 had a dose-dependent reversal for hyperalgesia with an estimated ED₅₀ value of 1.097 mg kg⁻¹. Moreover, compound 2 significantly suppressed the pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) in CFA-induced lesions. These protective effects of compound 2 on inflammatory pain were superior to those of GW405833, suggesting that compound 2 may be a promising therapeutic drug that needs further validation.

中文翻译：

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具有N-乙基吗啉部分作为CB2受体激动剂的吲哚化合物，用于疼痛的抗炎处理：合成和生物学评估。

CB2受体在镇痛和抗发炎中起关键作用。为了开发具有高效率和选择性的新型CB2激动剂，设计，合成和生物学评估了一系列具有N-乙基吗啉部分的吲哚衍生物（化合物1–56）。化合物1，2，3，46和53在低纳摩尔浓度表现出高的CB 2受体的亲和力和良好的受体选择性（EC ₅₀（CB1）/ EC ₅₀（CB2）大于1000）。活性最高的化合物（化合物2）在体外比标准药物GW405833更有效对CB2受体的激动作用。更重要的是，在CFA引起的炎症性痛觉过敏的大鼠模型中，化合物2在给药后12小时内具有有效的消炎镇痛作用。在1小时的时间点，化合物2具有痛觉过敏的剂量依赖性逆转，估计的ED ₅₀值为1.097mg kg ^-1。此外，化合物2显着抑制了CFA诱导的病变中的促炎细胞因子（IL-1β，IL-6和TNF-α）。化合物2对炎症性疼痛的这些保护作用优于GW405833，这表明化合物2可能是有前途的治疗药物，需要进一步验证。