Identification of RXR antagonists and characterization of potent stimulation of ST 13 preadipocyte differentiation

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Retinoid X receptor (RXR) ligands PA451 and PA452 are RXR pan-antagonist and HX531 is RXR pan-antagonist with retinoic acid receptor (RAR) pan-antagonist. Ligand displacement assay elucidate that these RXR antagonist displaced natural ligand 9-cis-retinoic acid from recombinant RXR strongly. Two-hybrid assay in mammalian cells demonstrated that RXR antagonists inhibited ligand dependent RXR binding to coactivator SRC-1 (steroid receptor coactivator) dose dependently. These results indicate the compounds are full competitive antagonists of RXR, and the ideal antagonists are not produced until now. Although these RXR antagonists function as antagonist toward RXR : RAR heterodimer, as agonist toward RXR : PPARγ (peroxisome proliferator activated receptor). This agonism of RXR antagonists also demonstrates against endogenous RXR : PPARγ. Simultaneous treatment with RXR antagonists and PPARγ agonist enhance the transactivation of PPARγ response element (PPRE) via RXR : PPARγ and induction of ST 13 preadipocyte differentiation. A chimera PPARγ receptor (PPARγ-RARγ) was constructed which ligand-binding domain of PPARγ has been replacing RARγ. The agonistic action of these RXR antagonists on RXR : PPAR exchange to antagonistic action on RXR : PPAR-RAR chimera receptor. These results suggest that amphypathic activity appeared in these RXR antagonists is depend on the structure of ligand binding domain of heterodimer partner. This is the first report of RXR antagonist-mediated agonism of PPARγ activity.