THE TOXICITY AND GLYCAEMIC PROPERTIES OF A NUMBER OF AMIDINE AND GUANIDINE DERIVATIVES

¹ From the Department of Pharmacology, University of Sheffield

1. Twenty-three amidine and two guanidine compounds belonging to five different classes have been examined for toxicity to mice and rabbits and their effect on carbohydrate metabolism has been studied.

2. Certain of these compounds after a preliminary period of hyperglycaemia produced marked hypoglycaemia, whilst others produced hyperglycaemia only.

3. The two most active hypoglycaemic compounds were sebacamidine and n-decane-1:10 diamindine. Neither of these compounds was as active as synthalin and neither produced hypoglycaemia in any but lethal doses.

4. It is shown in a homologous series of diamidines that the toxicity and hypoglycaemic properties increase with the number of methylene groups uniting the amidine residues and that maximum activity occurs where either 8 or 10 such groups are present.

5. Where hypoglycaemia did occur it was not insulin-like in character, and was probably due to liver damage. It is suggested that the immediate effect of the hepatic injury is to deplete the liver of its stores of glycogen and to increase the blood sugar. Later, normal glyconeogenesis is prevented resulting in hypoglycaemia.

6. The extent of the liver and kidney damage was followed by amino acid and blood urea determinations and by histological examination.

7. It is suggested that amidine hyperglycaemia may, in part, be due to sympathetic stimulation.

8. Various inferences are drawn on the relationship of chemical structure to hypoglycaemic and toxic action.

9. None of the compounds examined possess any value as hypoglycaemic drugs for use in clinical medicine.