Oxytocin analogues with combined high smooth muscle and negligible antidiuretic activities. Investigation of position 7 in neurohypophyseal hormones

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Abstract
The proline residue in position 7 of oxytocin occupies one of the 4 corner positions in the 2 .beta. turns proposed for the preferred conformation of the pituitary hormone. Synthetic modifications of the residues in these corner positions will probably yield analogues in which 1 or more of the biological activities of the parent hormone is highly accentuated in terms of potency relative to other activities. In a continued effort to test this hypothesis the following analogues of oxytocin were prepared: [7-glycine]oxytocin, [1-.beta.-mercaptopropionic acid, 7-glycine]oxytocin, [7-alanine]oxytocin and [1-.beta.-mercaptopropionic acid, 7-alanine]oxytocin. These peptides possess the following specific activities, respectively: rat uterotonic, 65 .+-. 2, 355 .+-. 3, 22 .+-. 1, 123 .+-. 4; avian vasodepressor, 5.3 .+-. 0.8, 17 .+-. 0.4, 4.8 .+-. 0.1, 9.8 .+-. 0.5; rat antidiuretic, < 0.01, 0.062 .+-. 0.006, 0.081 .+-. 0.01, 0.17 .+-. 0.01; rat pressor, 0.3, 0.5, 0.4, 0.5 unit/mg. The analogues retain high uterotonic activity but exhibit strongly diminished renal and vascular activities relative to oxytocin. Especially noteworthy is [1-.beta.-mercaptopropionic acid, 7-glycine]oxytocin with its high uterotonic activity but very low antidiuretic and pressor activities.