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Future Med Chem. 2010 Apr;2(4):575-86. doi: 10.4155/fmc.10.10.

Antidiabetic sulfonylureas modulate farnesoid X receptor activation and target gene transcription.

Author information

1
Institute of Pharmaceutical Chemistry/ZAFES/LiFF, Goethe-University Frankfurt Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany.

Abstract

BACKGROUND:

The sulfonylureas glibenclamide and glimepiride are oral antidiabetic drugs that stimulate insulin secretion by closing pancreatic ATP-dependent potassium channels. The farnesoid X receptor (FXR) is a ligand-activated transcription factor that regulates the expression of several target genes involved in bile acid metabolism and lipid and glucose homeostasis.

METHODS:

In this study we investigated the potential effects of sulfonylureas on the signaling of FXR using a reporter-gene assay, real-time qPCR and computational methods such as molecular docking and molecular dynamic simulations.

RESULTS:

We demonstrate that glibenclamide and glimepiride modulate FXR activation in a reporter-gene assay and induce FXR target genes in HepG2 cells. Within the docking experiments and molecular dynamics simulation, we found glibenclamide interacting with the ligand-binding domain of FXR and with helix 12.

CONCLUSION:

Glibenclamide and glimepiride are potential ligands of FXR and modulate activation and signaling.

PMID:
21426008
DOI:
10.4155/fmc.10.10
[Indexed for MEDLINE]

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