Discovery of Norisoboldine Analogue III11 as a Novel and Potent Aryl Hydrocarbon Receptor Agonist for the Treatment of Ulcerative Colitis

The
aryl hydrocarbon receptor (AhR) is a transcript factor, belonging
to the basic helix-loop-helix-Per-ARNT-SIM family, is closely associated
with health and diseases. Targeting AhR is an emerging therapeutic
strategy for various diseases. Norisoboldine (NOR), which is the main
alkaloid of Linderae Radix, has been known to activate AhR. Unfortunately,
the oral bioavailability (F) of NOR is only 2.49%.
To improve the chemical efficacy and bioavailability, we designed
and synthesized NOR analogues. Using various in vitro assays, 2-methoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-9-ol (III11) was discovered as a potent AhR agonist. Compound III11 enhanced the expression of AhR
downstream target genes, triggered AhR nuclear translocation, and
promoted differentiation of regulatory T cells. More importantly, III11 exhibited good bioavailability
(F = 87.40%) and remarkable therapeutic effects in
a mouse model of ulcerative colitis at a dosage of 10 mg/kg. These
findings may serve as a reference for the design of novel AhR agonists
against immune and inflammatory diseases.

芳香烃受体（AhR）作为一种转录因子，隶属于基本螺旋-环-螺旋-Per-ARNT-SIM家族，其与人类健康及疾病密切相关。针对AhR的靶向治疗策略正逐渐成为多种疾病治疗的新兴策略。诺瑞丁（NOR），作为 Linderae Radix 中的主要生物碱，已被证实能够激活AhR。遗憾的是，NOR的口服生物利用度（F）仅为2.49%。为了提升化学功效和生物利用度，我们设计并合成了NOR类似物。通过多种体外实验，我们发现2-甲氧基-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉-9-醇（III11）是一种高效的AhR激动剂。化合物III11能够增强AhR下游靶基因的表达，诱导AhR向细胞核的转移，并促进调节性T细胞的分化。更重要的是，III11在溃疡性结肠炎小鼠模型中表现出良好的生物利用度（F = 87.40%）和显著的疗效，剂量为10 mg/kg。这些发现可能为设计针对免疫和炎症疾病的 novel AhR 激动剂提供参考。