Comparative evaluation of the biological characteristics of a novel retinoid X receptor agonist and bexarotene
Retinoid X receptor (RXR) is a crucial and distinctive member of the nuclear receptor superfamily, which is involved in regulating various physiological processes. RXR agonists have the potential to treat Alzheimer's disease (AD). In this study, we identified a novel RXR agonist superior to existing drugs after extensively exploring the biological properties of 6-hydroxy-3'-propyl-[1,1'-biphenyl]-3-propanoic acid (6OHA), a compound synthesized in our laboratory based on the structure of magnaldehyde B. 6OHA exhibited higher selectivity for RXRa over retinoic acid receptor (RARa) and lower transcriptional activity for RXRg compared to the existing RXR agonist bexarotene (Bex). RNA-sequencing analysis, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathway analyses suggest that 6OHA and Bex exhibit similar gene expression patterns but have distinct transcriptional effects; 6OHA was more closely associated with chemotaxis and response to stimuli compared to Bex. Pharmacokinetic studies revealed that 6OHA exhibited faster intestinal absorption, reached higher concentrations in the brain and liver shortly after oral dministration, and was cleared from the body more rapidly than Bex, subsequently inducing target gene transcription in the brain. Bex increased serum triglyceride and decreased serum thyrotropin and free thyroxine levels, whereas 6OHA did not induce these adverse effects, attributable to the distinct properties of 6OHA as an RXR agonist compared to Bex. Our results highlight 6OHA as a promising RXR agonist for treating AD without any adverse effects. Overall design: Mouse microglial MG5 cells were treated with 6OHA or Bex at a concentration of 10 µM for 6 h, followed by extraction of total RNA. We then performed gene expression profiling using RNA-seq data from cells treated with 6OHA or Bex or untreated control (n=3). Bexarotene (Bex), an established retinoid X receptor (RXR) agonist, has demonstrated neuroprotective and anti-neuroinflammatory effects, suggesting its potential for Alzheimer's disease (AD) treatment. However, concerns remain regarding the serious adverse effects associated with Bex, including hypertriglyceridemia, hypothyroidism, and hepatomegaly. In this study, we investigated the differences in agonist activity between 6OHA, a newly synthesized RXR agonist in our laboratory, and Bex, with the goal of identifying alternative RXR agonists that may be suitable for the treatment or prevention of AD. Comparative gene expression profiling analysis of RNA-seq data for MG5 cells treated with 6OHA or BEX, or untreated cells.