Using the proposed conformation of vasopressin thought to be preferred when the mammalian antidiuretic hormone is bound to its renal receptor, an analogue, [1-d-mercaptopropionic acid,2-phenylalanine,7-(3,4-dehydroproline) ] arginine-vasopressin, was designed that contained three synthetic modifications. It posessed a rat antidiuretic potency of 13000 ± 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. ]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:
Replacement of the aliphatic isoleucine residue in position 3 of oxytocin (the first corner position of the beta-turn in the 20-membered ring of the solution conformation of the hormone) by phenylalanine has been shown to result in analogues with reduced affinity and intrinsic activity when tested by the individual dose-response procedure on the isolated rat uterus. Studies of effects of structural modifications have been extended to include two additional beta-turn corner positions. First, the dose-response behavior of [Leu4]oxytocin and [Phe4]oxytocin, two analogues in which the Glu4 side chain in the second corner position of the beta-turn in the 20-membered ring has been substituted by hydrophobic and bulky groups, was compared with that of oxytocin. Second, the solid-phase synthesis and biological properties of [Phe3,Leu4,Met8]oxytocin and [Phe3,4,Met8]oxytocin are described. The presence of leucine or phenylalanine in position 4 evokes a drastic reduction in both the affinity and intrinsic uterotonic activity of the resulting analogues, with phenylalanine significantly more effective in reducing intrinsic activity than leucine (p less than 0.001).
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