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）是一种转录因子，隶属于基本螺旋-环-螺旋-Per-ARNT-SIM家族，与人类健康及疾病密切相关。针对AhR的治疗策略是多种疾病治疗领域的新兴策略。去甲二氢莲叶碱（NOR），为 Linderae Radix 中的主要生物碱，已知可激活AhR。遗憾的是，NOR的口服生物利用度（F）仅为2.49%。为了提升其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，2-甲氧基-5,6,6a,7-四氢-4H-二苯并[de,g]喹啉-9-醇（III11）被发现是一种高效的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，以应对免疫和炎症性疾病提供参考。