Effects of new hypoglycemic agent 2-piperazinyl-4-methyl-amino-5-methylthieno [2,3-d]pyrimidine dihydrochloride hydrate.

The antidiabetic effects of 2-piperazinyl-4-methylamino-5-methylthieno [2,3-d]pyrimidine dihydrochloride hydrate (Compound-(I] were investigated in various animals and in various conditions. Compound-(I) is a new hypoglycemic agent structurally unrelated to sulfonylurea and biguanide. It produced dose dependent hypoglycemic effects (10-100 mg/kg) in rats and mice under fed, fasted and glucose tolerated states. However, it was ineffective in fasted guinea pigs even when given at 100 mg/kg. In normal fed rats and mice, hypoglycemic effects of Compound-(I) were estimated to be 3-19 times and 12-70 times more potent than tolbutamide and phenformin, respectively. Compound-(I) also produced hypoglycemic action in streptozocin diabetic rats and genetically diabetic KK mice. Especially, its hypoglycemic effect was observed at the dose as low as 3 mg/kg p.o. in KK mice. However, elevation of blood lactate was accompanied by lowering of blood glucose after oral administration of Compound-(I) in normal rats and mice and in streptozocin diabetic rats, while these effects were not observed in guinea pigs. In addition, plasma insulin significantly increased after administration of Compound-(I) in both normal and KK mice, while this increase in plasma insulin was not so prominent in fed rats. This elevation in plasma insulin might be produced by alpha 2-adrenergic antagonism at pancreatic B cell as Compound-(I) suppressed epinephrine induced hyperglycemia by elevating plasma insulin. In conclusion, Compound-(I) seems mainly to produce hypoglycemic action through extrapancreatic mechanism which increases blood lactate associated with anaerobic glycolysis or inhibition of gluconeogenesis. In addition, elevation of plasma insulin also might be responsible for hypoglycemic effects.