The retinoid X receptors and their ligands

Abstract

This chapter presents an overview of the current status of studies on the structural and molecular biology of the retinoid X receptor subtypes α, β, and γ (RXRs, NR2B1–3), their nuclear and cytoplasmic functions, post-transcriptional processing, and recently reported ligands. Points of interest are the different changes in the ligand-binding pocket induced by variously shaped agonists, the communication of the ligand–bound pocket with the coactivator binding surface and the heterodimerization interface, and recently identified ligands that are natural products, those that function as environmental toxins or drugs that had been originally designed to interact with other targets, as well as those that were deliberately designed as RXR-selective transcriptional agonists, synergists, or antagonists. Of these synthetic ligands, the general trend in design appears to be away from fully aromatic rigid structures to those containing partial elements of the flexible tetraene side chain of 9-cis-retinoic acid.

Insulin-like growth factor binding protein-3 (IGFBP-3): Novel ligands mediate unexpected functions

“…RXRα is a member of the class II nuclear hormone receptors, and typically acts either as a homodimer or, more commonly, as a heterodimer with other members of this group including the retinoic acid receptors (RARs), the vitamin D receptor VDR, the thyroid hormone receptor TR, liver X receptors (LXRs) and peroxisome proliferator-activated receptors (PPARs) (Dawson and Xia 2012). This important study revealed IGFBP-3 as a potential transcriptional regulator, activating effects mediated through the RXR response element but inhibiting signaling through the RAR response element (RARE, activated by ligand binding to RXR-RAR heterodimers) (Liu et al 2000).…”

Diarylamines Incorporating Hexahydrophenalene or Octahydrobenzoheptalene as Retinoid X Receptor (RXR)-Specific Agonists

“…Indeed, RXR ligands together with RAR ligands have potential therapeutic value in a variety of immunological and neurodegenerative disorders. [8][9][10] Many synthetic RXR-selective agonists have been reported, 4,5) and diarylamine-type ligands, such as PA024, show very potent activity.11) Therefore, building on the structures of our previously developed potent and subtype-selective RAR agonists, in the present work we synthesized a series of diarylamine ligands incorporating a tricyclic hydrophobic moiety, i.e., hexahydrophenalene or octahydrobenzoheptalene, as candidate RXR agonists. The target compounds were synthesized as follows.…”

“…This is of interest, because few RXR subtype-selective ligands have been developed. 4,5) These compounds do not show any activity towards RARs even at concentrations above 1000 nM, and are thus activators of RXRs. Dose-response curves of representative compounds are shown in Fig.…”

“…Indeed, RXR ligands together with RAR ligands have potential therapeutic value in a variety of immunological and neurodegenerative disorders. [8][9][10] Many synthetic RXR-selective agonists have been reported, 4,5) and diarylamine-type ligands, such as PA024, show very potent activity.…”

“…It is believed that the activation of RXRs alone does not cause any specific transactivation; rather RXRs act as heterodimers with RARs, peroxisome proliferator-activated receptors (PPARs), liver X receptor (LXR) and other nuclear receptors. 4,5) RXR-specific agonists alone cannot activate RXR-RAR heterodimers, but act as retinoid synergists that dose-dependently and robustly enhance the potency of RAR agonists. Thus, selective ligands specific for RARs and specific for RXRs are required for both biological studies and therapeutic purposes.…”