Hajime Iwai

Inhibition of the protein kinase by adenine compounds: Competitive inhibition with respect to ATP

Summary Rat liver adenosine 3′,5′-monophosphate ( cAMP )-dependent protein kinase was inhibited by 5×10−4M of adenine, adenosine, ADP and AMP, when assayed in the presence of 2×10−5M ATP. High concentrations of cAMP itself were inhibitory. The adenine compounds also inhibited the cAMP-independent form of the protein kinase. The inhibition of both cAMP-dependent and -independent forms of protein kinase was abolished by higher concentrations (5×10−4M) of ATP. It was concluded from the kinetic studies that the adenine compounds inhibited the protein kinase competitively with respect to ATP and they had no inhibitory effect on the activation step by cAMP.

Hypoglycemic activity of l-α-(3,4- dimethoxyphenethylaminomethyl)-2- hydroxybenzylalcohol 12 fumarate (TA-078) in the mouse, rat and dog

Abstract l -α-(3,4-Dimethoxyphenethylaminomethyl)-2-hydroxybenzylalcohol 1 2 fumarate (TA-078) is a new hypoglycemic agent structurally different from any existing hypoglycemic drug. It depresses the rise of blood glucose when it is orally administered to glucose-loaded mice, rats and beagle dogs at minimal doses of 1, 10 and 2.5 mg/kg, respectively. In contrast with tolbutamide, TA-078 hardly affected fasting blood glucose levels in rats and dogs and only weakly reduced fasting blood glucose levels in mice. Oral administration of TA-078 to KK mice also improved glucose tolerance, while no improvement was observed in streptozotocin-diabetic rats. TA-078 elevated plasma immunoreactive insulin (IRI) levels in mice and rats soon after its oral administration. In fasted rats, TA-078 caused only a transient increase in plasma IRI but did not affect plasma immunoreactive glucagon (IRG) levels in the early phase after its administration. On the other hand, tolbutamide induced a sustained increase in plasma IRI and a transient but marked decrease in plasma IRG. In perfused rat pancreas, TA-078 stimulated insulin secretion. The stimulation by 10 μg/ml TA-078 in the perfusion liquid required the presence of a normal concn (5.6 mM) of glucose, whereas the same concn of tolbutamide stimulated insulin release even at a low glucose concn (2.8 mM).