Suppression of natriferic activity of the vasopressin molecule by modifications in positions 1, 2 and 4.

The capacity of five synthetic analogs of [8-arginine] vasopressin (AVP) to stimulate frog skin sodium transport (natriferic activity) was characterized electrophysiologically using the method of short-circuit current, and compared to that of synthetic AVP. The analogs used were [8-arginine] vasopressins modified in positions 1 and 2: [1-(1-mercapto-4-tert-butylcyclohexaneacetic acid)] AVP (I); [1-(1-mercapto-4-methylcyclohexaneacetic acid)] AVP (II); [1-(1-mercapto-4-methylcyclohexaneacetic acid)-2-O-methyltyrosine] AVP (III); and in position 4: [1-(1-mercaptocyclohexaneacetic acid)-4-arginine] AVP (IV); [1-(2-mercaptopropionic acid)-4-arginine] AVP (V). The addition of synthetic vasopressins I, II and V to the frog skin resulted in a weaker stimulation of the skin sodium transport, measured as the level of the short-circuit current (Isc), as compared to that induced by synthetic AVP. In relation to natriferic activity, analogs III and IV did not change the electrical parameters of the skin. It is concluded that introduction of cyclic structure at the beta-carbon in position 1 of the vasopressin molecule decreased its natriferic activity by about 70%. The same reduction of the activity was caused by the replacement of the glutamine residue in position 4 with arginine, and deamination in position 1. Cyclic structure bound in position 1 together with methylation of tyrosine in position 2 resulted in a full suppression of natriferic activity. Similarly, introduction of cyclic group in position 1 in combination with substitution of glutamine in position 4 with arginine totally abolished natriferic activity.