New in Vitro Tools to Study Human Constitutive Androstane Receptor (CAR) Biology: Discovery and Comparison of Human CAR Inverse Agonists
- 1 November 2011
- journal article
- research article
- Published by American Chemical Society (ACS) in Molecular Pharmaceutics
- Vol. 8 (6), 2424-2433
- https://doi.org/10.1021/mp2003658
Abstract
The human constitutive androstane receptor (CAR, NR1I3) is one of the key regulators of xenobiotic and endobiotic metabolism. The unique properties of human CAR, such as the high constitutive activity and the complexity of signaling, as well as the lack of functional and predictive cell-based assays to study the properties of the receptor, have hindered the discovery of selective human CAR ligands. Here we report a novel human CAR inverse agonist, 1-[(2-methylbenzofuran-3-yl)methyl]-3-(thiophen-2-ylmethyl) urea (S07662), which suppresses human CAR activity, recruits the corepressor NCoR in cell-based assays, and attenuates the phenytoin- and 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO)-induced expression of CYP2B6 mRNA in human primary hepatocytes. The properties of S07662 are also compared with those of known human CAR inverse agonists by using an array of different in vitro and in silico assays. The identified compound S07662 can be used as a chemical tool to study the biological functions of human CAR and also as a starting point for the development of new drugs for various conditions involving the receptor.Keywords
This publication has 57 references indexed in Scilit:
- Rational quantitative structure–activity relationship (RQSAR) screen for PXR and CAR isoform-specific nuclear receptor ligandsChemico-Biological Interactions, 2010
- The “Phantom Effect” of the Rexinoid LG100754: Structural and Functional InsightsPLOS ONE, 2010
- Regulation of drug-metabolizing enzymes by xenobiotic receptors: PXR and CARAdvanced Drug Delivery Reviews, 2010
- Activation of nuclear receptor CAR ameliorates diabetes and fatty liver diseaseProceedings of the National Academy of Sciences of the United States of America, 2009
- Current Industrial Practices in Assessing CYP450 Enzyme Induction: Preclinical and ClinicalThe AAPS Journal, 2008
- The Peripheral Benzodiazepine Receptor Ligand 1-(2-Chlorophenyl-methylpropyl)-3-isoquinoline-carboxamide Is a Novel Antagonist of Human Constitutive Androstane ReceptorMolecular Pharmacology, 2008
- Nuclear Receptor Coregulators: Judges, Juries, and Executioners of Cellular RegulationMolecular Cell, 2007
- The role of the nuclear receptor constitutive androstane receptor in the pathogenesis of non-alcoholic steatohepatitisGut, 2007
- CAR and PXR: The xenobiotic-sensing receptors☆Steroids, 2006
- VMD: Visual molecular dynamicsJournal of Molecular Graphics, 1996