Stereoselective synthesis, biological evaluation, and modeling of novel bile acid-derived G-protein coupled bile acid receptor 1 (GP-BAR1, TGR5) agonists

Bioorg Med Chem. 2015 Apr 1;23(7):1613-28. doi: 10.1016/j.bmc.2015.01.048. Epub 2015 Feb 11.

Abstract

GP-BAR1 (also known as TGR5), a novel G-protein coupled receptor regulating various non-genomic functions via bile acid signaling, has emerged as a promising target for metabolic disorders, including obesity and type II diabetes. However, given that many bile acids (BAs) are poorly tolerated for systemic therapeutic use, there is significant need to develop GP-BAR1 agonists with improved potency and specificity and there also is significant impetus to develop a stereoselective synthetic methodology for GP-BAR1 agonists. Here, we report the development of highly stereo-controlled strategies to investigate a series of naturally occurring bile acid derivatives with markedly enhanced GP-BAR1 activity. These novel GP-BAR1 agonists are evaluated in vitro using luciferase-based reporter and cAMP assays to elucidate their biological properties. In vivo studies revealed that the GP-BAR1 agonist 23(S)-m-LCA increased intestinal GLP-1 transcripts by 26-fold. Additionally, computational modeling studies of selected ligands that exhibit enhanced potency and specificity for GP-BAR1 provide information on potential binding sites for these ligands in GP-BAR1.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Bile Acids and Salts / chemical synthesis*
  • Bile Acids and Salts / pharmacology
  • Drug Evaluation, Preclinical / methods
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular*
  • Molecular Sequence Data
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / genetics
  • Stereoisomerism

Substances

  • Bile Acids and Salts
  • GPBAR1 protein, human
  • Receptors, G-Protein-Coupled