Identification and Characterization of a Leoligin-Inspired Synthetic Lignan as a TGR5 Agonist

The G-protein coupled bile acid receptor 1 (GPBAR1 or TGR5) is the major cell membrane receptor for bile acids regulating metabolic and immunological functions. Its pharmacological modulation has been shown to alleviate inflammatory diseases, such as type 2 diabetes and atherosclerosis. The naturally occurring lignan leoligin and structural analogues have shown anti-inflammatory effects in vitro. However, the underlying molecular targets are still unknown. In this study, we identify the natural product-inspired synthetic structural analogue of leoligin, LT-188A (<b>1</b>), as a novel nonsteroidal TGR5 agonist. LT-188A (<b>1</b>) induced cyclic adenosine monophosphate (cAMP) accumulation and cAMP response element (CRE)-dependent luciferase activity in a concentration- and TGR5-dependent manner. Consistently, LT-188A (<b>1</b>) inhibited activation of the pro-inflammatory transcription factor nuclear factor κB (NFκB) only in TGR5 expressing cells. In macrophages, LT-188A (<b>1</b>) reduced the expression levels of pro-inflammatory cytokines and the production of nitric oxide (NO) as determined by qPCR and the Griess assay, respectively. We showed that LT-188A (<b>1</b>) decreased the levels of production of these inflammatory mediators in macrophages. In conclusion, we demonstrate that LT-188A (<b>1</b>) is a novel natural product-inspired TGR5 agonist with promising anti-inflammatory in vitro bioactivity in relevant cellular assays representing a promising tool compound with potential for further development.