Introduction: Peroxisome proliferator-activated receptor γ  (PPARγ ) plays a key role in glucose, which is a ligand-mediated transcription factor. The lipid homeostasis often serves as a pharmacological target for new drug discovery and development.
Materials and Methods: In the research, we synthesized a series of piperine derivatives and then used a fluorescence polarization-based PPARγ  ligand screening assay to evaluate the agonistic activity of PPARγ . Then, we cultured human normal hepatocytes, which were treated with 100μM compounds 2a, 2t or 3d. Then, the levels of PPARγ  gene were determined so as to show whether the compounds could activate or inhibit the expression of PPARγ .
Results: A total of 30 piperine derivatives were synthesized and evaluated. Compound 2a was identified as a potential PPARγ  agonist with IC₅₀ at 2.43 μM, which is 2 times more potent than the positive control rosiglitazone with IC₅₀ at 5.61μM. The human hepatocytes cells were cultured and treated with compounds 2a, 2t or 3d as described in the “Materials and Methods” section. We found that compounds 2a, 2t and 3d could activate PPARγ  by 11.8, 1.9 and 7.0 times compared with the “blank”, with compound 2a activation being the most significant. Molecular docking studies indicated that the piperine derivative 2a stably interacts with the amino acid residues of the PPARγ  complex active site, which is consistent with the results of the in vitro PPARγ  ligand screening assay.
Keywords: PPARγ , piperine derivatives, ligand screening assay, molecular docking