SYNTHESIS AND BIOLOGICAL-ACTIVITIES OF ARGININE-VASOPRESSIN ANALOGS DESIGNED FROM A CONFORMATION-ACTIVITY APPROACH

Using the proposed conformation of vasopressin thought to be preferred when the mammalian antidiuretic hormone is bound to its renal receptor, an analogue, [1-β-mercaptopropionic acid, 2-phenylalanine, 7-(3, 4-dehydroproline)] arginine-vasopressin, was designed that contained three synthetic modifications. It posessed a rat antidiuretic potency of 13 000 ± 1250 units/mg, no measurable rat pressor activity, an in vitro rat uterotonic potency of 6.0 ± 0.6 units/mg, and an avian vasodepressor potency of 2.9 ± 0.5 units/mg. The strong dissociation of an apparently very high antidiuretic activity of this analogue from its other biological activities prompted the synthesis of the singly and doubly modified analogues of this series of 3, 4-dehydroproline-containing derivatives. [1-β-Mercaptopropionic acid, 7-(3, 4-dehydroproline)]arginine-vasopressin, [2-phenylalanine, 7-(3, 4-dehydroproline)]arginine-vasopressin, and [7-(3, 4-dehydroproline)]arginine-vasopressin were found to have the following specific activities (units/mg), respectively: rat antidiuretic, 4134 ± 306, 1541 ± 336, 1260 ± 126; rat pressor, 240 ± 4.5, 63.8 ± 3.9, 255 ± 23; rat uterotonic, 69 ± 5, 0.80 ± 0.11, 40.6 + 4.7; avian vasodepressor, 345 ± 19, 4.2 ± 0.9, 76.9 ± 48. Using the same synthetic procedure, arginine-vasopressin was prepared in an overall yield of 51% with rat antidiuretic and pressor potencies of 511 ± 61 and 519 ± 13, respectively. Renal clearance studies revealed that arginine-vasopressin and [1-β-mercaptopropionic acid, 2-phenylalanine, 7-(3, 4-dehydroproline)]arginine-vasopressin affect water and electrolyte handling by the kidney through a similar mechanism, but that the decrease in urine flow seen for the synthetic analogue is augmented by a decrease in glomerular filtration rate. © 1979, American Chemical Society. All rights reserved.