Pharmacological effects of introducing a double bond into a binding site of oxytocin. Analogues with L-3,4-dehydroproline in position 7.
The side chain of the proline residue in position 7 of oxytocin has been proposed as a binding site of the hormone for the uterotonic receptor. This is the first 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-mecaptopropionic 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 uterotinic, 1071 +/- 59, 1066 +/- 95, 880 +/- 180; avian 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 ocytocin. 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. These data would seem to support the hypothesis that the introduction of unsatuation into binding element of a peptide hormone can enhance the affinity of the hormone for some of its receptors and thereby its selectivity.
D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects*; D002645:Chickens; D004231:Diuresis / Q000187:drug effects*; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D008968:Molecular Conformation; D010121:Oxytocin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D011392:Proline / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014590:Uterine Contraction / Q000187:drug effects*
D010121:Oxytocin; D011392:Proline