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Sensors 2015, 15(4), 9265-9276;

The Use of the LanthaScreen TR-FRET CAR Coactivator Assay in the Characterization of Constitutive Androstane Receptor (CAR) Inverse Agonists

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University in Prague, Heyrovského 1203, Hradec Kralove CZ500 05, Czech Republic
Author to whom correspondence should be addressed.
Academic Editor: Niko Hildebrandt
Received: 27 February 2015 / Revised: 3 April 2015 / Accepted: 14 April 2015 / Published: 21 April 2015
(This article belongs to the Special Issue FRET Biosensors)
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The constitutive androstane receptor (CAR) is a critical nuclear receptor in the gene regulation of xenobiotic and endobiotic metabolism. The LanthaScreenTM TR-FRET CAR coactivator assay provides a simple and reliable method to analyze the affinity of a ligand to the human CAR ligand-binding domain (LBD) with no need to use cellular models. This in silico assay thus enables the study of direct CAR ligands and the ability to distinguish them from the indirect CAR activators that affect the receptor via the cell signaling-dependent phosphorylation of CAR in cells. For the current paper we characterized the pharmacodynamic interactions of three known CAR inverse agonists/antagonists—PK11195, clotrimazole and androstenol—with the prototype agonist CITCO (6-(4-chlorophenyl)imidazo[2,1-b][1,3] thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime) using the TR-FRET LanthaScreenTM assay. We have confirmed that all three compounds are inverse agonists of human CAR, with IC50 0.51, 0.005, and 0.35 μM, respectively. All the compounds also antagonize the CITCO-mediated activation of CAR, but only clotrimazole was capable to completely reverse the effect of CITCO in the tested concentrations. Thus this method allows identifying not only agonists, but also antagonists and inverse agonists for human CAR as well as to investigate the nature of the pharmacodynamic interactions of CAR ligands. View Full-Text
Keywords: TR-FRET; terbium; constitutive androstane receptor; pharmacodynamics interactions TR-FRET; terbium; constitutive androstane receptor; pharmacodynamics interactions

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Carazo, A.; Pávek, P. The Use of the LanthaScreen TR-FRET CAR Coactivator Assay in the Characterization of Constitutive Androstane Receptor (CAR) Inverse Agonists. Sensors 2015, 15, 9265-9276.

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