Synthesis of O-alkylated lysine-vasopressins, inhibitors of the antidiuretic response to lysine-vasopressin.

[Mpa1,Tyr(Et)2]-LVP (1-deamino-2-O-ethyltyrosine-8-lysine-vasopressin), [Mpa1,Tyr(n-Pr)2]-LVP, [Tyr(n-Bu)2]-LVP, [Mpa1,Tyr(n-Bu)2]-LVP, and [Mpa1,Tyr(n-hexyl)2]-LVP were synthesized in solution by the p-nitrophenyl ester method. The previously prepared [Tyr(Et)2]-LVP was resynthesized. All compounds possessed weak agonistic properties in both antidiuretic (0.5-2.0 IU/mumol) and pressor (0.5-3.0 IU/mumol) assays. In the rat none of the analogues inhibited the antidiuretic action of LVP when the two substances were given together in a single injection. However, when administered in low subthreshold doses, most of the deamino compounds suppressed the antidiuresis induced by a continuous infusion of LVP. Complete inhibition was obtained with [Mpa1,Tyr(Et)2]-LVP. The antagonistic potency seemed to decrease with increasing size of the alkyl substituent and [Mpa1,Tyr(n-hexyl)2]-LVP showed no antagonism. The molar inhibitor-LVP ratio for maximal inhibition was well below 100. Neither of the two amino analogues showed a clear-cut antagonism in the antidiuretic assay. Furthermore, none of the reported compounds was antagonistic to LVP in the rat pressor assay.