Distinct properties and advantages of a novel peroxisome proliferator-activated protein [gamma] selective modulator.

@article{Berger2003DistinctPA,
  title={Distinct properties and advantages of a novel peroxisome proliferator-activated protein [gamma] selective modulator.},
  author={Joel P. Berger and Ann E Petro and Karen L Macnaul and Linda J. Kelly and Bei B. Zhang and Karen M. Richards and Alex Elbrecht and Bruce A Johnson and Gaochao Zhou and Thomas W. Doebber and Chhabi Biswas and Mona Parikh and Neelam Sharma and Michael R. Tanen and Gl{\'o}ria M. Thompson and John R. Ventre and Alan D. Adams and Ralph T. Mosley and Richard S. Surwit and David E. Moller},
  journal={Molecular endocrinology},
  year={2003},
  volume={17 4},
  pages={
          662-76
        }
}
Antidiabetic thiazolidinediones (TZDs) and non-TZD compounds have been shown to serve as agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma). Here, we report the identification and characterization of a novel non-TZD selective PPARgamma modulator (nTZDpa). nTZDpa bound potently to PPARgamma with high selectivity vs. PPARalpha or PPARdelta. In cell-based assays for transcriptional activation, nTZDpa served as a selective, potent PPARgamma partial agonist and was able to… 
The Differential Interactions of Peroxisome Proliferator-Activated Receptor γ Ligands with Tyr473 Is a Physical Basis for Their Unique Biological Activities
TLDR
The results directly demonstrate the important role of Tyr473 in mediating the interaction of full agonists but not SPPARγMs with the PPARγ LBD, thereby providing a precise molecular determinant for their differing pharmacologies.
T2384, a Novel Antidiabetic Agent with Unique Peroxisome Proliferator-activated Receptor γ Binding Properties*
TLDR
When administered to diabetic KKAy mice, T2384 rapidly improved insulin sensitivity in the absence of weight gain, hemodilution, and anemia characteristics of treatment with rosiglitazone (a TZD), consistent with the hypothesis that interactions between ligands and specific regions of the receptor ligand-binding pocket might selectively trigger a subset of receptor-mediated biological responses leading to the improvement of insulin sensitivity.
Molecular characterization of new selective peroxisome proliferator-activated receptor gamma modulators with angiotensin receptor blocking activity.
TLDR
SPPARM activity by ARBs could retain the metabolic efficacy of PPARgamma activation with reduction in adverse effects exerting in parallel AT1 receptor blockade, and may provide a new therapeutic option for better cardiovascular risk management in metabolic diseases.
A New Class of Peroxisome Proliferator-activated Receptor Agonists with a Novel Binding Epitope Shows Antidiabetic Effects*
TLDR
It is concluded that the 2-BABA binding mode can be used to design isoform-specific PPAR modulators with biological activity in vivo, and the 5-substituted 2-benzoylaminobenzoic acids (2-BABAs) are described.
A Selective Peroxisome Proliferator-Activated Receptor γ Modulator with Distinct Fat Cell Regulation Properties
TLDR
FK614 behaves as an SPPARM with differential effects on the activation of PPARγ at each stage of adipocyte differentiation and may contribute to its enhanced insulin sensitization in differentiating adipocytes and to reduced insulin resistance at the stage of lipid hypertrophy.
Mode of Peroxisome Proliferator-Activated Receptor γ Activation by Luteolin
TLDR
It is proposed that activities of luteolin are related to its singular binding mode, that anti-inflammatory activity does not require H12 stabilization, and that the structure can be useful in developing safe selective PPARγ modulators.
Review of the Structural and Dynamic Mechanisms of PPARγ Partial Agonism
TLDR
Partial agonists of PPARγ have been shown to retain favourable insulin sensitizing effects while exhibiting little to no side effects and thus represent a new potential class of therapeutics for the treatment of T2DM.
Unique Interactome Network Signatures for Peroxisome Proliferator-activated Receptor Gamma (PPARγ) Modulation by Functional Selective Ligands
TLDR
Tandem mass spectrometry analysis revealed unique, partially overlapping, compound- and subcellular compartment-specific complexes that are putative coregulators of PPARγ.
...
...

References

SHOWING 1-10 OF 51 REFERENCES
L-764406 Is a Partial Agonist of Human Peroxisome Proliferator-activated Receptor γ
TLDR
A novel non-TZD ligand for PPARγ is shown to be a potent and first known partial agonist for this receptor and a critical functional role for Cys313, and helix 3, in contributing to ligand binding and subsequent agonist-induced conformational changes is suggested.
Novel Peroxisome Proliferator-activated Receptor (PPAR) γ and PPARδ Ligands Produce Distinct Biological Effects*
TLDR
Novel, non-thiazolidinedione agonists for PPARγ and PPARδ that were identified by radioligand binding assays improve hyperglycemia and hypertriglyceridemia in vivo and are able to potentiate preadipocyte differentiation.
A peroxisome proliferator-activated receptor gamma ligand inhibits adipocyte differentiation.
TLDR
X-ray crystallography revealed that GW0072 occupied the ligand-binding pocket by using different epitopes than the known PPAR agonists and did not interact with the activation function 2 helix, establishing an approach to the design of PPAR ligands with modified biological activities.
The mechanisms of action of PPARs.
TLDR
The current state of knowledge regarding the molecular mechanisms of PPAR action and the involvement of the PPARs in the etiology and treatment of several chronic diseases is presented.
A Synthetic Antagonist for the Peroxisome Proliferator-activated Receptor γ Inhibits Adipocyte Differentiation*
TLDR
These results provide the first pharmacological evidence that PPARγ activity is required for the hormonally induced differentiation of adipogenic cells.
Ligand-induced stabilization of PPARgamma monitored by NMR spectroscopy: implications for nuclear receptor activation.
TLDR
Activation of this nuclear receptor is a result of a population shift of a dynamic ensemble of conformations, rather than a two-state switch from an inactive to an active conformation.
Gene Expression Profile of Adipocyte Differentiation and Its Regulation by Peroxisome Proliferator-Activated Receptor-γ Agonists.
TLDR
Both mRNA and protein levels for β-catenin were down-regulated in 3T3-L1 adipocytes compared with fibroblasts and were further decreased by treatment of adipocy...
A Selective Peroxisome Proliferator-Activated Receptor-γ (PPARγ) Modulator Blocks Adipocyte Differentiation but Stimulates Glucose Uptake in 3T3-L1 Adipocytes
TLDR
A novel PParγ ligand is identified that does not activate PPARγ but selectively and competitively blocks thiazolidinedione-induced PPAR� activation and adipocyte conversion and antagonizes target gene activation as well as repression in agonist-treated 3T3-L1 adipocytes.
...
...