The Effects of Guanidine and Alkylguanidines on the Energy Transfer Reactions of Mitochondria*

Considerable attention has been focused on the biological activity of guanidine derivatives from two main directions. Ever since the original report by Watanabe of the hypoglycemic properties of guanidine (3), derivatives of this compound have been investigated as possible therapeutic agents for the control of diabetic hyperglycemia. At least three such compounds, Synthalin (decamethylenediguanidine) (4)) DBI (phenethylbiguanide) (5)) and dimethylbiguanide (6)) have actually achieved limited clinical use as oral antidiabetic agents. Of more direct consequence in prompting the present study was Hollunger’s observation (7) that guanidine and its derivatives induce a unique and characteristic inhibition of mitochondrial processes in vitro associated with high energy phosphate bond formation. Previous studies directed toward accounting for the relationship between the hypoglycemic and inhibitory properties in vitro of guanidine derivatives (8-10) have not revealed its underlying basis. Nevertheless, the distinctiveness of the two concomitant properties of this class of compounds continues to suggest that they are linked mechanistically. It is hoped that ultimate clarification of this relationship will be facilitated by the information obtained in the current investigation. Hollunger found that high concentrations (> 0.01 M) of guanidine, as well as of its methyl and N , N-dimethyl derivatives, inhibit the respiration of phosphorylating mitochondria. Synthalin was observed to inhibit similarly but was more potent and differed slightly in the manner of the time course of its inhibition development (7). It seemed reasonable to attribute the increased effectiveness of Synthalin to the lipophilic decamethylene bridge. The starting point of the present investigation was to test this assumption by comparing the activities of a systematic series of substituted guanidines. It was also hoped that if such a study disclosed guanidine derivatives of increased potency, these would, in turn, facilitate future experiments designed to study the interaction of the guanidines with mitochondria in vitro. In addition, correlation of the structure and metabolic properties of the guanidines could provide useful information about the chemical and physical nature of the enzymatic reactions affected and of the reactive sites involved.