THE DESIGN OF POTENTIAL ANTIDIABETIC DRUGS - EXPERIMENTAL INVESTIGATION OF A NUMBER OF BETA-D-GLUCOSE ANALOG INHIBITORS OF GLYCOGEN-PHOSPHORYLASE

alpha-D-glucose is a weak inhibitor (K-i=1.7 mM) of glycogen phosphory lase (GP) and acts as physiological regulator of hepatic glycogen meta bolism; it binds to GP at the catalytic site and stabilizes the inacti ve T state of the enzyme promoting the action of protein phosphatase 1 and stimulating glycogen synthase. The three-dimensional structures o f T state rabbit muscle GPb and the GPb-alpha-D-glucose complex have b een exploited in the design of better regulators of GP that could shif t the balance between glycogen synthesis and glycogen degradation in f avour of the former Close examination of the catalytic site with alpha -D-glucose bound shows that there is an empty pocket adjacent to the b eta-1-C position. beta-D-glucose is a poorer inhibitor (K-i=7.4 mM) th an alpha-D-glucose, but mutarotation has prevented the binding of beta -D-glucose in T state GP crystals. A series of beta-D-glucose analogue s has been designed and tested in kinetic and crystallographic experim ents. Several compounds have been discovered that have an increased af finity for GP than the parent compound.