Bioactivity of glycogen phosphorylase inhibitors that bind to the purine nucleoside site
Φόρτωση...
Ημερομηνία
Συγγραφείς
Hampson, L. J.
Arden, C.
Agius, L.
Ganotidis, M.
Kosmopoulou, M. N.
Tiraidis, C.
Elemes, Y.
Sakarellos, C.
Leonidas, D. D.
Oikonomakos, N. G.
Τίτλος Εφημερίδας
Περιοδικό ISSN
Τίτλος τόμου
Εκδότης
Elsevier
Περίληψη
Τύπος
Είδος δημοσίευσης σε συνέδριο
Είδος περιοδικού
peer reviewed
Είδος εκπαιδευτικού υλικού
Όνομα συνεδρίου
Όνομα περιοδικού
Bioorg Med Chem
Όνομα βιβλίου
Σειρά βιβλίου
Έκδοση βιβλίου
Συμπληρωματικός/δευτερεύων τίτλος
Περιγραφή
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-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.
Περιγραφή
Λέξεις-κλειδιά
type-2 diabetes, glycogen phosphorylase, flavopiridols, inhibitors, glycogen metabolism, hepatocytes., rat hepatocytes, allosteric site, in-vivo, glucose, liver, inactivation, glucose-6-phosphate, metabolism, activation, kinase
Θεματική κατηγορία
Παραπομπή
Σύνδεσμος
<Go to ISI>://000242063500017
http://ac.els-cdn.com/S096808960600616X/1-s2.0-S096808960600616X-main.pdf?_tid=7415422358703879d83064bc08d28f38&acdnat=1333029088_77b71843fa0bebf7c52560227b239025
http://ac.els-cdn.com/S096808960600616X/1-s2.0-S096808960600616X-main.pdf?_tid=7415422358703879d83064bc08d28f38&acdnat=1333029088_77b71843fa0bebf7c52560227b239025
Γλώσσα
en
Εκδίδον τμήμα/τομέας
Όνομα επιβλέποντος
Εξεταστική επιτροπή
Γενική Περιγραφή / Σχόλια
Ίδρυμα και Σχολή/Τμήμα του υποβάλλοντος
Πανεπιστήμιο Ιωαννίνων. Σχολή Θετικών Επιστημών. Τμήμα Χημείας