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，与人类健康与疾病密切相关。针对AhR的靶向治疗策略已成为治疗多种疾病的新兴疗法。诺里索丁（NOR），系八角茴香根的主要生物碱，已知能够激活AhR。遗憾的是，NOR的口服生物利用度（F）仅为2.49%。为了提升化学活性和生物利用度，我们设计并合成了NOR的类似物。通过多种体外实验，我们发现了2-甲氧基-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉-9-醇（III11）是一种强效的AhR激动剂。化合物III11能够增强AhR下游靶基因的表达，引发AhR的核转位，并促进调节性T细胞的分化。更重要的是，III11在10 mg/kg的剂量下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。这些发现可为新型AhR激动剂的设计提供参考，以应对免疫和炎症性疾病。