Synthesis and some pharmacological properties of deamino[4-threonine,8-D-arginine]vasopressin and deamino[8-D-arginine]vasopressin, highly potent and specific antidiuretic peptides, and [8-D-arginine]vasopressin and deamino-arginine-vasopressin

Abstract

Deamino[4-threonine,8-D-arginine]vasopressin (dTDAV), deamino[8-D-arginine]vasopressin (dDAVP), [8-D-arginine]vasopressin (DAVP), and deamino-arginine-vasopressin (dAVP) were synthesized by the solid-phase method and tested in the rat for their biological activities. dTDAVP has an antidiuretic potency of 793 .+-. 95 units/mg and undetectable vasopressor activity, < 0.02 unit/mg. The antidiuretic-pressor (A/P) ratio of dTDAVP is greater than 39,000. dDAVP has an antidiuretic potency of 1200 .+-. 126 units/mg and a vasopressor potency of 0.39 .+-. 0.02; its A/P ratio is thus 3000. DAVP has an antidiuretic potency of 253 .+-. 44 units/mg, a vasopressor potency of 1.1 .+-. 0.04 units/mg and an A/P ratio of 240. The A/P ratios of dDAVP and DAVP are much higher than those originally reported. dAVP has an antidiuretic potency of 1745 .+-. 385 units/mg, a vasopressor potency of 346 .+-. 13 and an A/P ratio of 5; values are in general agreement with those in the literature. Threonine substitution brought about a significant enhancement in antidiuretic specificity, a finding entirely consistent with earlier observations that enhancement of lipophilicity at position 4 alone or in combination in arginine-vasopressin can lead to enhanced antidiuretic specificity.