Conformation-activity studies of oxytocin. Effects of structural modifications at corner positions of the .beta.-turns on the uterotonic activity

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Abstract
Replacement of the aliphatic isoleucine residue in position 3 of oxytocin (the 1st corner position of the .beta.-turn in the 20-membered ring of the solution conformation of the hormone) by phenylalanine apparently resulted in analogues with reduced affinity and intrinsic activity when tested by the individual dose-response procedure on isolated rat uterus. Studies of effects of structural modifications were extended to include 2 additional .beta.-turn corner positions. First, the dose-response behavior of [Leu4]oxytocin and [Phe4]oxytocin, 2 analogues in which the Glu4 side chain in the 2nd corner position of the .beta.-turn in the 20-membered ring was 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 the affinity and intrinsic uterotonic activity of the resulting analogues, with phenylalanine significantly more effective in reducing intrinsic activity than leucine (P < 0.001).