Τόμος 12 (1994) – Τεύχος 3 – Άρθρο 1 – Επιθεώρηση Κλινικής Φαρμακολογίας και Φαρμακοκινητικής-Ελληνική Έκδοση – Volume 12 (1994) – Issue 3 – Article 1 – Epitheorese Klinikes Farmakologias και Farmakokinetikes-Greek Edition

 

Τίτλος – Title

Σχεδιασμός Δυνάμει Αντιδιαβητικών Φαρμάκων: Παράγωγα της βD-γλυκόζης ως Αναστολείς της Γλυκογονικής Φωσφορυλάσης

The Design of Potential Antidiabetic Drugs: β-D-Glucose Analogue Inhibitors of Glycogen Phosphorylase

Συγγραφέας – Author

Ν.Γ. Οικονομάκος1, Μ. Κοντού1, Σ.Ε. Ζωγράφος1, Δ.Δ. Κουτρά1, L.N. Johnson2, K.A. Watson2, E.P. Mitchell2, G.W.J. Fleet3, J.C. Son3 και C.J.F. Bichard3

1 Ινστιτούτο Βιολογικών Ερευνών και Βιοτεχνολογίας, Εθνικό Ιδρυμα Ερευνών, Βασ. Κωνσταντίνου 48, Αθήνα 11635, Ελλάδα 2 Laboratory of Molecular Biophysics, University of Oxford, South Parks Road, Oxford OX1 3QU, 3 Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QY, UK

N.G. Oikonomakos1, Μ. Kontou1, S.E. Zographos1, D.D. Koutra1, L.N. Johnson2, K.A. Watson2, E.P. Mitchell2, G.W.J. Fleet3, J.C. Son3 and C.J.F. Bichard3

1 Institute of Biological Research & Biotechnol­ogy, The National Hellenic Research Foundation, 48 Vas. Constantinou Ave, Athens 11635, Greece, 2 Laboratory of Molecular Biophysics, University of Oxford, South Parks Road, Oxford OX1 3QU, 3 Dyson Perrins Laboratory, University of Ox­ford, South Parks Road, Oxford OX1 3QY, UK

Παραπομπή – Citation

Οικονομάκος,Ν.Γ., Κοντού,Μ.,  Ζωγράφος,Σ.Ε., Κουτρά,Δ.Δ., Johnson,L.N.,  Watson,K.A., Mitchell,E.P., Fleet,G.W.J., Son,J.C., Bichard,C.J.F. : Σχεδιασμός Δυνάμει Αντιδιαβητικών Φαρμάκων: Παράγωγα της βD-γλυκόζης ως Αναστολείς της Γλυκογονικής Φωσφορυλάσης , Επιθεώρηση Κλιν. Φαρμακολ. Φαρμακοκινητ. 12 : 103-122 (1994)

Oikonomakos,Ν.G., Kontou,Μ.,  Zographos,S.Ε., Koutra,D.D., Johnson,L.N.,  Watson,K.A., Mitchell,E.P., Fleet,G.W.J., Son,J.C., Bichard,C.J.F. : The Design of Potential Antidiabetic Drugs: β-D-Glucose Analogue Inhibitors of Glycogen Phosphorylase , Epitheorese Klin. Farmakol. Farmakokinet. 12 : 103-122 (1994)

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Ελληνικά – Greek

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Λέξεις κλειδιά – Keywords

α-D-γλυκόζη, β-D-γλυκόζη, Παράγωγα βD-γλυκόζης, αναστολείς, γλυκογονική φωσφορυλάση

α-D-glucose, β-D-glucose, β-D-glucose analogues, inhibitors, glycogen phosphorylase
Λοιποί Όροι – Other Terms

Άρθρο

Article

Περίληψη – Summary

Η γλυ­κό­ζη, φυ­σιο­λο­γι­κός ρυθ­μι­στής του με­τα­βο­λι­σμού του γλυ­κο­γό­νου στο ή­παρ, α­να­στέλ­λει (ά­με­σα) τη δρά­ση της γλυ­κο­γο­νι­κής φω­σφο­ρυ­λά­σης και ε­νερ­γο­ποι­ε­ί (έμ­με­σα) τη δρά­ση της γλυ­κο­γο­νι­κής συν­θε­τά­σης. Παρά­γω­γα της γλυ­κό­ζης, με ι­σχυρό­τε­ρη α­να­σταλ­τι­κή δρά­ση έ­να­ντι της γλυ­κο­γο­νι­κής φω­σφο­ρυ­λά­σης, μπο­ρεί να έ­χουν κα­λύ­τε­ρες ρυθ­μι­στι­κές ι­διό­τη­τες, με­τα­το­πί­ζο­ντας την ι­σορ­ρο­πί­α με­τα­ξύ α­ποι­κο­δό­μη­σης και σύν­θε­σης γλυ­κο­γό­νου προς την κα­τεύ­θυν­ση της σύν­θε­σης, και ως εκ τού­του κλι­νι­κό εν­δια­φέ­ρον στην α­ντι­με­τώ­πι­ση του σακ­χα­ρώδη δια­βή­τη (τύ­που Ι­Ι), ό­που η α­δυ­να­μί­α κα­τα­στο­λής της πα­ρα­γω­γής γλυ­κό­ζης εί­ναι α­πό τις κύ­ριες εκ­δη­λώ­σεις της α­σθενεί­ας. Η γνώ­ση της τρισ­διά­στα­της δο­μής της γλυ­κο­γο­νι­κής φω­σφο­ρυ­λά­σης, σε υ­ψη­λή ευ­κρί­νεια, πα­ρέ­χει τη δυ­να­τό­τη­τα σχε­δια­σμού πα­ρα­γώ­γων γλυ­κό­ζης, με αυ­ξη­μέ­νη (συ­γκρι­τι­κά με τη γλυ­κό­ζη) συγ­γέ­νει­α σύν­δε­σης προς το εν­ζυ­μι­κό μό­ριο. Πε­ρι­γρά­φο­νται κι­νη­τι­κά και κρυ­σταλ­λο­γρα­φι­κά α­πο­τε­λέ­σμα­τα μιας νέ­ας σει­ράς α­να­στο­λέ­ων της GPb, πα­ρα­γώ­γων της β-D-γλυκό­ζης.

Glucose is a physiological regulator of hepatic glycogen metabolism and in­duces sequentially the inactivation of glycogen phosphorylase and the acivation of glycogen syn­thase. More potent glucose analogue inhibitors of glycogen phosphorylase have the potential to shift the balance between glycogen degradation and glycogen synthesis in favour of the latter and hence may provide new therapeutic agents for the treatment of diabetes, where failure to sup­press hepatic output of glucose is one of the ma­jor manifestations of the disease. A series of glu­cose analogues have been designed, synthesized and tested in kinetic and crystallographic binding studies with glycogen phosphorylase. Several re­lated compounds have been discovered that have an increased affinity for glycogen phosphorylase by 2 orders of magnitude than the parent glucose compound.

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