Conformation-activity studies of oxytocin. Effects of structural modifications at corner positions of the beta-turns on the uterotonic activity.
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).
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002645:Chickens; D003864:Depression, Chemical; D004231:Diuresis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D010121:Oxytocin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D014590:Uterine Contraction / Q000187:drug effects*
D010121:Oxytocin