Vasopressin antidiuretic agonist and antagonist activity in dogs: structural and stereochemical relationship between...

A series of vasopressin analogs with various amino acid tail modifications were tested for antidiuretic agonist and antagonist (water diuretic) activity in the water-loaded indomethacin-treated and hydropenic dogs, respectively. Changing the carboxy terminus from Cys6-Pro7-Arg8-NH2 in SK&F 101926 to Cys6-Arg7-NH2 or to D-Cys6-Pro7-Arg8-NH2 or to D- or L-Cys6-Arg7-D-Arg8-NH2 reduced antidiuretic agonist and increased water diuretic activity. Replacement of the sulfur atoms in the cysteine residues with methylene groups further reduced the antidiuretic agonist activity of all carboxy terminus-modified compounds which possessed full agonist activity. It also increased the water diuretic activity of those disulfide analogs with both weak agonist and antagonist activity. These results indicate that alterations in the geometry of the hexapeptide ring and in the stereochemical relationship between the ring and the carboxy terminus of the molecule substantially modify the in vivo agonist and antagonist activity of vasopressin analogs.