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Bioactivity of glycogen phosphorylase inhibitors that bind to the purine nucleoside site

Lookup NU author(s): Dr Laura Hampson, Dr Catherine ArdenORCiD, Professor Loranne Agius


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The bioactivity in hepatocytes of glycogen phosphorylase inhibitors that bind to the active site, the allosteric activator site and the indole carboxamide site has been described. However, the pharmacological potential of the purine nucleoside inhibitor site has remained unexplored. We report the chemical synthesis and bioactivity in hepatocytes of four new olefin derivatives of flavopiridol (1-4) that bind to the purine site. Flavopiridol and 1-4 counteracted the activation of phosphorylase in hepatocytes caused by AICAR (5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside), which is metabolised to an AMP analogue. Unlike an indole carboxamide inhibitor, the analogues 1 and 4 suppressed the basal rate of glycogenolysis in hepatocytes by allosteric inhibition rather than by inactivation of phosphorylase, and accordingly caused negligible stimulation of glycogen synthesis. However, they counteracted the stimulation of glycogenolysis by dibutyryl cAMP by both allosteric inhibition and inactivation of phosphorylase. Cumulatively, the results show key differences between purine site and indole carboxamide site inhibitors in terms of (i) relative roles of dephosphorylation of phosphorylase-a as compared with allosteric inhibition, (ii) counteraction of the efficacy of the inhibitors on glycogenolysis by dibutyryl-cAMP and (iii) stimulation of glycogen synthesis. © 2006 Elsevier Ltd. All rights reserved.

Publication metadata

Author(s): Hampson LJ, Arden C, Agius L, Ganotidis M, Kosmopoulou MN, Tiraidis C, Elemes Y, Sakarellos C, Leonidas DD, Oikonomakos NG

Publication type: Article

Publication status: Published

Journal: Bioorganic and Medicinal Chemistry

Year: 2006

Volume: 14

Issue: 23

Pages: 7835-7845

ISSN (print): 0968-0896

ISSN (electronic): 1464-3391

Publisher: Pergamon


DOI: 10.1016/j.bmc.2006.07.060


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