Structural changes in the arginine vasopressin molecule that prolong its antidiuretic action

Abstract

A number of structural analogues of neurohypophysial peptides produce antidiuretic responses of varying duration when injected SC into conscious rats with hereditary hypothalamic diabetes insipidus. Analogues containing arginine in the 8-position and lacking an N-terminal amino group all have markedly prolonged antidiuretic effects. Deamino analogues with other basic amino acids in the 8-position have effectsthat are prolonged to a lesser degree. Deamino-mesotocin has a slightly prolonged antidiuretic effect but deamino-oxytocin does not. Substituting amino acids with more lipophilic side-chains for the 4-glutamine in deamino-arginine-vasopressin further enhances the persistence of its antidiuretic action. Substituting 8-D-arginine for 8-L-arginine in vasopressin does not influence duration of action. Deamination is thus clearly the primary molecular change that endows arginine vasopressin analogues with greatly prolonged antidiuretic effects, while introducing more lipophilic side-chains in the 4-position may prolong these further. Substituting either a more lipophilic side-chain in position 4 or D-arginine in position 8 decreases vasopressor activity but not antidiuretic activity. When both types of substitution are made in deamino-arginine-vasopressin, the resultant analogue, l-deamino-[4-valine, 8-D-arginine]-vasopressin (dVDAVP) is highly active, the most specific antidiuretic peptide ever reported, and has greatly prolonged antidiuretic. © 1974 by The Endocrine Society.