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

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dc.contributor.authorHampson, L. J.en
dc.contributor.authorArden, C.en
dc.contributor.authorAgius, L.en
dc.contributor.authorGanotidis, M.en
dc.contributor.authorKosmopoulou, M. N.en
dc.contributor.authorTiraidis, C.en
dc.contributor.authorElemes, Y.en
dc.contributor.authorSakarellos, C.en
dc.contributor.authorLeonidas, D. D.en
dc.contributor.authorOikonomakos, N. G.en
dc.date.accessioned2015-11-24T16:53:06Z
dc.date.available2015-11-24T16:53:06Z
dc.identifier.issn0968-0896-
dc.identifier.urihttps://olympias.lib.uoi.gr/jspui/handle/123456789/9971
dc.rightsDefault Licence-
dc.subjecttype-2 diabetesen
dc.subjectglycogen phosphorylaseen
dc.subjectflavopiridolsen
dc.subjectinhibitorsen
dc.subjectglycogen metabolismen
dc.subjecthepatocytes.en
dc.subjectrat hepatocytesen
dc.subjectallosteric siteen
dc.subjectin-vivoen
dc.subjectglucoseen
dc.subjectliveren
dc.subjectinactivationen
dc.subjectglucose-6-phosphateen
dc.subjectmetabolismen
dc.subjectactivationen
dc.subjectkinaseen
dc.titleBioactivity of glycogen phosphorylase inhibitors that bind to the purine nucleoside siteen
heal.abstractThe 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-beta-D-ribofuranoside), which is metabolised to an AMP analogue. Unlike an indole carboxamide inhibitor, the analogues I 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. (c) 2006 Elsevier Ltd. All rights reserved.en
heal.accesscampus-
heal.fullTextAvailabilityTRUE-
heal.identifier.primaryDOI 10.1016/j.bmc.2006.07.060-
heal.identifier.secondary<Go to ISI>://000242063500017-
heal.identifier.secondaryhttp://ac.els-cdn.com/S096808960600616X/1-s2.0-S096808960600616X-main.pdf?_tid=7415422358703879d83064bc08d28f38&acdnat=1333029088_77b71843fa0bebf7c52560227b239025-
heal.journalNameBioorg Med Chemen
heal.journalTypepeer reviewed-
heal.languageen-
heal.publicationDate2006-
heal.publisherElsevieren
heal.recordProviderΠανεπιστήμιο Ιωαννίνων. Σχολή Θετικών Επιστημών. Τμήμα Χημείαςel
heal.typejournalArticle-
heal.type.elΆρθρο Περιοδικούel
heal.type.enJournal articleen

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