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 (1), as a novel nonsteroidal TGR5
agonist. LT-188A (1) induced cyclic adenosine monophosphate
(cAMP) accumulation and cAMP response element (CRE)-dependent luciferase
activity in a concentration- and TGR5-dependent manner. Consistently,
LT-188A (1) inhibited activation of the pro-inflammatory
transcription factor nuclear factor κB (NFκB) only in
TGR5 expressing cells. In macrophages, LT-188A (1) 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 (1) decreased the levels of production
of these inflammatory mediators in macrophages. In conclusion, we
demonstrate that LT-188A (1) 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.