Retinoids Selective for Retinoid X Receptor Response Pathways

Abstract

Retinoids have a broad spectrum of biological activities and are useful therapeutic agents. Their physiological activities are mediated by two types of receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). RARs, as well as several related receptors, require heterodimerization with RXRs for effective DNA binding and function. However, in the presence of 9-cis-retinoic acid, a ligand for both RARs and RXRs, RXRs can also form homodimers. A series of retinoids is reported that selectively activates RXR homodimers but does not affect RAR-RXR heterodimers and thus demonstrates that both retinoid response pathways can be independently activated.

Endogenous retinoid X receptors can function as hormone receptors in pituitary cells.

“…A CAT reporter gene containing the palindromic (inverted repeat) element TREp, which can be activated by both RARs and RXRs (47,66), was used. Figure 2A shows that as expected, RA and 9-cis RA activated transcription by both RARs and RXRs (38,44,47,66). However, SR11237 selectively activated RXRot-dependent transcription -22-fold over the control (vehicle alone) level, and RXR-y mRNAs were barely detectable in JEG-3 cells by Northern analysis (data not shown).…”

“…rGH mRNA levels were similarly increased when GH3 cells were treated with 9-cis RA. To more clearly identify the population of endogenous receptors mediating the effects of retinoids in GH3 cells, we synthesized the ketal retinoid SR11237, which has been previously shown to be RXR selective in transient transfection assays (38). Before using SR11237 as a tool to assess the ability of liganded RXR to regulate expression of endogenous genes, however, we felt it crucial to confirm its RXR specificity in multiple ways.…”

“…To determine whether RXR functions as a ligand-dependent hormone receptor in GH3 cells, we synthesized the ketal retinoid SR11237, previously shown to be RXR selective (38), and confirmed its RXR specificity by using a number of different criteria. SR11237 did not (38) was prepared from readily available starting material (56a).…”

“…SR11237 did not (38) was prepared from readily available starting material (56a). The identity and purity of the compound were verified by nuclear magnetic resonance and infrared spectroscopy and by melting point analysis.…”

Thiol dependent isomerization of all‐trans‐retinoic acid to 9‐cis‐retinoic acid

“…It can bind to a subset of retinoic acid receptors known as RXR receptors, as well as binding to RAR receptors [1][2][3]. The biological activity of 9-cis-retinoic acid is presumed to be distinct from that of the well-described alt-trans-retinoic acid [4][5][6].…”