Rational quantitative structure-activity relationship (RQSAR) screen for PXR and CAR isoform-specific nuclear receptor ligands

Chem Biol Interact. 2010 Dec 5;188(3):512-25. doi: 10.1016/j.cbi.2010.09.018. Epub 2010 Oct 20.


Constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are closely related orphan nuclear receptor proteins that share several ligands and target overlapping sets of genes involved in homeostasis and all phases of drug metabolism. CAR and PXR are involved in the development of certain diseases, including diabetes, metabolic syndrome and obesity. Ligand screens for these receptors so far have typically focused on steroid hormone analogs with pharmacophore-based approaches, only to find relatively few new hits. Multiple CAR isoforms have been detected in human liver, with the most abundant being the constitutively active reference, CAR1, and the ligand-dependent isoform CAR3. It has been assumed that any compound that binds CAR1 should also activate CAR3, and so CAR3 can be used as a ligand-activated surrogate for CAR1 studies. The possibility of CAR3-specific ligands has not, so far, been addressed. To investigate the differences between CAR1, CAR3 and PXR, and to look for more CAR ligands that may be of use in quantitative structure-activity relationship (QSAR) studies, we performed a luciferase transactivation assay screen of 60 mostly non-steroid compounds. Known active compounds with different core chemistries were chosen as starting points and structural variants were rationally selected for screening. Distinct differences in agonist versus inverse agonist/antagonist effects were seen in 49 compounds that had some ligand effect on at least one receptor and 18 that had effects on all three receptors; eight were CAR1 ligands only, three were CAR3 only ligands and four affected PXR only. This work provides evidence for new CAR ligands, some of which have CAR3-specific effects, and provides observational data on CAR and PXR ligands with which to inform in silico strategies. Compounds that demonstrated unique activity on any one receptor are potentially valuable diagnostic tools for the investigation of in vivo molecular targets.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antifungal Agents / chemistry
  • Antifungal Agents / metabolism
  • Biphenyl Compounds / chemistry
  • Biphenyl Compounds / metabolism
  • Cell Line, Tumor
  • Drug Evaluation, Preclinical
  • Histamine Antagonists / chemistry
  • Histamine Antagonists / metabolism
  • Humans
  • Ligands
  • Phenolphthalein / chemistry
  • Phenolphthalein / metabolism
  • Pregnane X Receptor
  • Protein Binding
  • Protein Isoforms / metabolism
  • Quantitative Structure-Activity Relationship*
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Receptors, Steroid / metabolism*
  • Stilbenes / chemistry
  • Stilbenes / metabolism
  • Substrate Specificity
  • Terphenyl Compounds / chemistry
  • Terphenyl Compounds / metabolism


  • Antifungal Agents
  • Biphenyl Compounds
  • Histamine Antagonists
  • Ligands
  • Pregnane X Receptor
  • Protein Isoforms
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • Stilbenes
  • Terphenyl Compounds
  • diphenyl
  • constitutive androstane receptor
  • Phenolphthalein