Pharmacological effects of introducing a double bond into a binding site of oxytocin. Analogs with L-3,4-dehydroproline in position 7

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Abstract
The side chain of the proline residue in position 7 of oxytocin was proposed as a binding site of the hormone for the uterotonic receptor. This is the 1st in a series of studies in which the possibility is explored that amino acid residues located at such sites and bearing unsaturated side chains may contribute more strongly to binding than neutral, aliphatic side chains. To test this hypothesis [7-(L-3,4-dehydroproline)]oxytocin, [1-.beta.-mercaptopropionic acid,7-(L-3,4-dehydroproline)]oxytocin and [1-L-.alpha.-hydroxy-.beta.-mercaptopropionic acid,7-(L-3,4-dehydroproline)]oxytocin were prepared by the solid-phase technique of peptide synthesis. Some of the pharmacological properties of the analogues were determined, and the following specific activities, respectively, were found: rat uterotonic, 1071 .+-. 59, 1066 .+-. 95, 880 .+-. 180; avian [chicken] vasodepressor, 548 .+-. 10, 1008 .+-. 42, 1295 .+-. 62; rat antidiuretic 5.9 .+-. 0.2, 23.3 .+-. 1.1, 76.7 .+-. 2.3. All analogues possess a lower rat pressor activity than oxytocin. Compared to oxytocin, [7-(L-3,4-dehydroproline)]oxytocin exhibits a parallel displacement of the cumulative uterotonic log dose vs. response curve toward lower concentration (pD2 = 9.26 vs. 8.63) but elicits the same maximum response. The introduction of unsaturation into a binding element of a peptide hormone can enhance the affinity of the hormone for some of its receptors and thereby its selectivity.
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