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

类视黄酸受体（RXR）配体PA451和PA452是RXR泛拮抗剂，HX531是RXR泛拮抗剂和视黄酸受体（RAR）泛拮抗剂。配体置换实验表明，这些RXR拮抗剂强烈地置换了重组RXR中的天然配体9-顺式维甲酸。在哺乳动物细胞中进行的双杂交实验表明，RXR拮抗剂可以剂量依赖性地抑制RXR与类固醇受体共激活剂SRC-1的结合。这些结果表明，这些化合物是RXR的完全竞争拮抗剂，目前尚未产生理想的拮抗剂。虽然这些RXR拮抗剂作为RXR: RAR异源二聚体的拮抗剂，但作为RXR: PPARγ（过氧化物酶体增殖物激活受体）的激动剂。RXR拮抗剂的这种激动作用也显示出对内源性RXR: PPARγ的作用。RXR拮抗剂和PPARγ激动剂同时治疗可通过RXR: PPARγ增强PPARγ反应元件（PPRE）的转激活，并诱导ST 13前脂肪细胞分化。构建了一个嵌合体PPARγ受体（PPARγ-RARγ），其配体结合结构域取代了RARγ。这些RXR拮抗剂对RXR: PPAR的拮抗作用转化为对RXR: PPAR- rar嵌合体受体的拮抗作用。这些结果表明，这些RXR拮抗剂出现的两性病变活性取决于异二聚体伴侣的配体结合域结构。这是关于RXR拮抗剂介导的PPARγ活性激动作用的第一篇报道。

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.