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

Abstract

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 (III 11 ) was discovered as a potent AhR agonist. Compound III 11 enhanced the expression of AhR downstream target genes, triggered AhR nuclear translocation, and promoted differentiation of regulatory T cells. More importantly, III 11 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.

Discovery of a Highly Potent Oxysterol Receptor GPR183 Antagonist Bearing the Benzo[d]thiazole Structural Motif for the Treatment of Inflammatory Bowel Disease (IBD)

“…After a week of acclimatization, mice were randomly divided into five groups: vehicle, 3% DSS (MP Biomedicals) + vehicle, 3% DSS + 5-ASA (200 mg/kg), 3% DSS + compound 33 (3 mg/kg and 10 mg/kg), with 6 mice in each group. An aqueous solution of 0.5% sodium carboxymethyl cellulose was used for 5-ASA preparation, according to previous studies. , DSS was administered for 5 days beforehand. Subsequently, mice were orally administered with corresponding compounds.…”

Activation of the aryl hydrocarbon receptor in inflammatory bowel disease: insights from gut microbiota

“…Nowadays, various therapies targeting the microbiome for IBD such as probiotics, antibiotics, fecal microbiota transplantation (FMT), defined enteral nutritional therapy (ENT), and gene manipulation have been discovered and demonstrated to have varying degrees of efficacy (Glassner et al, 2020). The positive effect of AHR agonists in colitis models has also been proved (Benson and Shepherd, 2011;Furumatsu et al, 2011;Monteleone et al, 2011;Singh et al, 2011;Huang et al, 2013;Qiu and Zhou, 2013;Hanieh, 2014;Ji et al, 2015;Park et al, 2015;Aoki et al, 2018;Lv et al, 2018a;Lv et al, 2018b;Yu et al, 2018;Marafini et al, 2019;Singh et al, 2019;Chen et al, 2020;Liu et al, 2020;Lin et al, 2023). However, both the markable immunotoxic effects and even carcinogenesis properties of most recognized exogenous synthetic AHR ligands have been elucidated (Murray et al, 2014;Stockinger et al, 2021;Abudahab et al, 2023;, which limited clinical widespread application in IBD patients.…”

“…Accordingly, AHR activity has been proposed as a potential therapeutic target for IBD. Several studies have confirmed that colitis can be alleviated by AHR ligands through activating the AHR (Hanieh, 2014;Lv et al, 2018a;Lv et al, 2018b;Yu et al, 2018;Marafini et al, 2019;Chen et al, 2020;Lin et al, 2023). However, most of the recognized exogenous synthetic AHR ligands have been associated with toxicity, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and polycyclic aromatic hydrocarbon (PAH) (Abudahab et al, 2023), which hamper the widespread application of AHR-ligand therapy and forces us to find non-toxic natural AHR ligands.…”