The pharmacological actions of amidine [—C(NH2):NH2] derivatives given most attention in this review are those affecting blood pressure, smooth and skeletal muscle tone, and metabolism. An account has been given of the distribution of pressor, reflex depressor, vasoconstrictor, hypoglycaexnic, antibacterial, and certain other forms of pharmacological activity amongst amidine derivatives and compounds chemically related to them. Attention has been restricted largely to compounds of fairly simple structure, particularly those belonging to aliphatic homologous series, in order to emphasize factors which are believed to be of major importance in determining activity.
Basic strength is one such factor. The characteristic properties of amidine derivatives as a class are those of amidinium cations. These cations are thought to compete with cations of physiological importance for anionic sites on or in cells.
Molecular size is also of major importance. It would be expected on chemical grounds that an amidinium ion with a long hydrocarbon chain would be better able than a lower homologue to become concentrated in the phase in which the drug receptors lie, and also to remain in contact with the receptors for longer periods on the average in the face of competition from other cations. Hence it is not surprising that some, though by no means all, pharmacological actions of amidine derivatives increase in intensity and duration when a homologous series is ascended (up to a "cut-off" imposed by extreme water-insolubility). These actions are probably ones which depend upon the occupation of, as distinct from the act of combination with, drug receptors. The distribution of such properties as pressor activity can be explained most simply by assuming that stimulant actions of amidine derivatives are brought about by a quantal process, occurring as the result of the drug's making contact with the receptor and being prevented from recurring for so long as the two remain in contact.
The characteristics of the drug receptor appear to be highly important for some forms of activity but not for others. Thus, it seems important for possession of strong reflex depressor activity that the size and shape of the molecule should be comparable to that of 5-hydroxytryptamine. On the other hand, the ability of numerous amines and amidine derivatives to exert trypanocidal and antibacterial actions implies that little specificity of structure is needed to permit interaction with certain other receptors.