The Synthesis and Pharmacological Properties of 4-Decarboxamido-8-lysine-vasopressin, 5-Decarboxamido-8-lysine-vasopressin, and Their 1-Deamino Analogues

• Published in: The Journal of biological chemistry Vol. 242; no. 20; pp. 4806 - 4812
• Main Authors: Gillessen, D, Du Vigneaud, V
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 25.10.1967
• Subjects: Animals; Chickens; Lysine; Male; Models, Structural; Oxytocin - pharmacology; Rats; Vasoconstrictor Agents - pharmacology; Vasopressins - chemical synthesis; Vasopressins - pharmacology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/S0021-9258(18)99528-1

Analogues of 8-lysine-vasopressin in which the carboxamide groups on the glutamine and asparagine residues at positions 4 and 5 are replaced individually by hydrogen have been synthesized by the p -nitrophenyl ester method of peptide synthesis and tested for some of the pharmacological activities characteristic of this pressor-antidiuretic hormone of the posterior pituitary gland. The 4-decarboxamido-8-lysine-vasopressin ([4-α-aminobutyric acid]-8-lysine-vasopressin) has an antidiuretic potency of approximately 700 units per mg, nearly 3 times the potency of 8-lysine-vasopressin. It also possesses approximately 25% of the avian vasodepressor activity, 20% of the oxytocic activity, and 4% of the pressor activity of 8-lysine-vasopressin, whereas 5-decarboxamido-8-lysine-vasopressin ([5-alanine]-8-lysine-vasopressin) does not exhibit an appreciable degree of any of these activities. Thus the carboxamide group of the asparagine residue at position 5 of 8-lysine-vasopressin appears to play an important role in determining the pharmacological effects of the hormone. The corresponding 1-deamino analogues of the 4- and 5-decarboxamido-8-lysine-vasopressins, in which the free amino group on the half-cystine residue at position 1 is replaced by hydrogen, have also been synthesized. 1-Deamino-4-decarboxamido-8-lysine-vasopressin possesses extremely high antidiuretic activity (730 units per mg), low pressor activity (3.5 units per mg), and the same oxytocic and avian vasodepressor activities as 4-decarboxamido-8-lysine-vasopressin, whereas 1-deamino-5-decarboxamido-8-lysine-vasopressin is practically inactive. The successive replacement of the carboxamide and amino groups on the glutamine and half-cystine residues at positions 4 and 1, respectively, of 8-lysine-vasopressin thus results in a striking enhancement of antidiuretic activity coupled with a marked decrease in pressor activity.