G Protein-Coupled Estrogen Receptor-Mediated Anti-Inflammatory and Mucosal Healing Activity of a Trimethylpyridinol Analogue in Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is characterized by
abnormal immune
responses, including elevated proinflammatory cytokines, such as tumor
necrosis factor-α (TNFα) and interleukin-6 (IL-6) in the
gastrointestinal (GI) tract. This study presents the synthesis and
anti-inflammatory evaluation of 2,4,5-trimethylpyridin-3-ol analogues,
which exhibit dual inhibition of TNFα- and IL-6-induced inflammation.
Analysis using in silico methods, including 3D shape-based
target identification, modeling, and docking, identified G protein-coupled
estrogen receptor 1 (GPER) as the molecular target for the most effective
analogue, 6-26, which exhibits remarkable
efficacy in ameliorating inflammation and restoring colonic mucosal
integrity. This was further validated by surface plasmon resonance
(SPR) assay results, which showed direct binding to GPER, and by the
results showing that GPER knockdown abolished the inhibitory effects
of 6-26 on TNFα and IL-6 actions.
Notably, 6-26 displayed no cytotoxicity,
unlike G1 and G15, a well-known GPER agonist and an antagonist, respectively,
which induced necroptosis independently of GPER. These findings suggest
that the GPER-selective compound 6-26 holds
promise as a therapeutic candidate for IBD.