Discovery and SAR of Natural-Product-Inspired RXR Agonists with Heterodimer Selectivity to PPARδ‑RXR

A known natural product,
magnaldehyde B, was identified as an agonist
of retinoid X receptor (RXR) α. Magnaldehyde B was isolated
from Magnolia obovata (Magnoliaceae) and synthesized
along with more potent analogs for screening of their RXRα agonistic
activities. Structural optimization of magnaldehyde B resulted in
the development of a candidate molecule that displayed a 440-fold
increase in potency. Receptor–ligand docking simulations indicated
that this molecule has the highest affinity with the ligand binding
domain of RXRα among the analogs synthesized in this study.
Furthermore, the selective activation of the peroxisome proliferator-activated
receptor (PPAR) δ-RXR heterodimer with a stronger efficacy compared
to those of PPARα-RXR and PPARγ-RXR was achieved in luciferase
reporter assays using the PPAR response element driven reporter (PPRE-Luc).
The PPARδ activity of the molecule was significantly inhibited
by the antagonists of both RXR and PPARδ, whereas the activity
of GW501516 was not affected by the RXR antagonist. Furthermore, the
molecule exhibited a particularly weak PPARδ agonistic activity
in reporter gene assays using the Gal4 hybrid system. The obtained
data therefore suggest that the weak PPARδ agonistic activity
of the optimized molecule is synergistically enhanced by its own RXR
agonistic activity, indicating the potent agonistic activity of the
PPARδ-RXR heterodimer.