The nuclear receptors peroxisome proliferator-activated receptor γ (PPARγ) and its hetero-dimerization partner retinoid X receptor α (RXRα) 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 PPARγ to obtain ligands with more favorable properties than currently used drugs. Magnolol was previously described as dual agonist of PPARγ and RXRα. Here we show the structure-based rational design of a linked magnolol dimer within the ligand binding domain of PPARγ and its synthesis. Furthermore, we evaluated its binding properties and functionality as a PPARγ agonist in vitro with the purified PPARγ 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 PPARγ ligand binding domain than magnolol (K i values of 5.03 and 64.42 nM, respectively). Regarding their potency to transactivate a PPARγ-dependent luciferase gene both compounds were equally effective. This is likely due to the PPARγ specificity of the newly designed magnolol dimer and lack of RXRα-driven transactivation activity by this dimeric compound.

Department of Pharmacognosy University of Vienna Vienna Austria

Department of Pharmacognosy University of Vienna Vienna Austria Department of Biochemical Sciences Faculty of Pharmacy in Hradec Králové Charles University Hradec Králové Czech Republic

Department of Pharmacognosy University of Vienna Vienna Austria Institute of Genetics and Animal Breeding of the Polish Academy of Sciences Jastrzebiec Poland

Institute of Applied Synthetic Chemistry TU Wien Vienna Austria

Institute of Pharmacy Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck University of Innsbruck Innsbruck Austria

Institute of Pharmacy Pharmacognosy and Center for Molecular Biosciences Innsbruck University of Innsbruck Innsbruck Austria

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