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The Strathprints institutional repository is a digital archive of University of Strathclyde research outputs.

Strathprints serves world leading Open Access research by the University of Strathclyde, including research by the Strathclyde Institute of Pharmacy and Biomedical Sciences (SIPBS), where research centres such as the Industrial Biotechnology Innovation Centre (IBioIC), the Cancer Research UK Formulation Unit, SeaBioTech and the Centre for Biophotonics are based.

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Identification of peroxisome proliferator-activated receptor ligands from a biased chemical library

Brown, Peter J. and Smith-Oliver, Tracey A. and Charifson, Paul S. and Tomkinson, Nicholas C. O. and Fivush, Adam M. and Sternbach, Daniel D. and Wade, Laura E. and Orband-Miller, Lisa and Parks, Derek J. and Blanchard, Steven G. (1997) Identification of peroxisome proliferator-activated receptor ligands from a biased chemical library. Chemistry and Biology, 4 (12). pp. 909-918. ISSN 1074-5521

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Abstract

The peroxisome proliferator-activated receptors (PPARs) were cloned as orphan members of the nuclear receptor superfamily of transcription factors. The identification of subtype-selective ligands for PPARα and PPARγ has led to the discovery of their roles in the regulation of lipid metab. and glucose homeostasis. No subtype-selective PPARδ ligands are available and the function of this subtype is currently unknown. A three-component library was designed in which one of the monomers was biased towards the PPARs and the other two monomers were chosen to add chem. diversity. Synthesis and screening of the library resulted in the identification of pools with activity on each of the PPAR subtypes. Deconvolution of the pools with the highest activity on PPARδ led to the identification of GW 2433 as the first high-affinity PPARδ ligand. [3H]GW 2433 is an effective radioligand for use in PPARδ competition-binding assays. Conclusions: The synthesis of biased chem. libraries is an efficient approach to the identification of lead mols. for members of sequence-related receptor families. This approach is well suited to the discovery of small-mol. ligands for orphan receptors.