Linked magnolol dimer as a selective PPAR gamma agonist - Structure-based rational design, synthesis, and bioactivity evaluation
Abstract
The nuclear receptors peroxisome proliferator-activated receptor gamma (PPAR gamma) and its hetero-dimerization partner retinoid X receptor alpha (RXR alpha) are considered as drug targets in the treatment of diseases like the metabolic syndrome and diabetes mellitus type 2. Effort has been made to develop new agonists for PPAR gamma to obtain ligands with more favorable properties than currently used drugs.
Magnolol was previously described as dual agonist of PPAR gamma and RXR alpha. Here we show the structure-based rational design of a linked magnolol dimer within the ligand binding domain of PPAR gamma and its synthesis.
Furthermore, we evaluated its binding properties and functionality as a PPAR gamma agonist in vitro with the purified PPAR gamma ligand binding domain (LBD) and in a cell-based nuclear receptor transactivation model in HEK293 cells. We determined the synthesized magnolol dimer to bind with much higher affinity to the purified PPAR gamma ligand binding domain than magnolol (K-i values of 5.03 and 64.42 nM, respectively).
Regarding their potency to transactivate a PPAR gamma-dependent luciferase gene both compounds were equally effective. This is likely due to the PPAR gamma specificity of the newly designed magnolol dimer and lack of RXRa-driven transactivation activity by this dimeric compound.