Active-site studies of neurohypophyseal hormones: synthesis and pharmacological properties of [5-(N4,N4-dimethylasparagine)]oxytocin.
Synthesis and biological properties of [5-(N4,N4-dimethylasparagine)]oxytocin are reported. In this analogue, the hydrogens of the primary carboxamide moiety in the side chain of the asparagine residue in position 5 of the posterior pituitary hormone oxytocin have been replaced by two methyl groups. The protected nonapeptide intermediate was prepared by a stepwise procedure using solution techniques. The analogue possesses 4.60 +/- 0.03 units/mg (mean +/- SEM) uterotonic activity on the isolated rat uterine horn and 9.14 +/- 0.03 units/mg of avian vasodepressor activity. Moreover, it displays an identical intrinsic activity in the in vitro rat uterotonic assay as oxytocin, when tested in the presence of either 0.5 mM Ca2+ (standard assay conditions) or at reduced levels of Ca2+ (0.3, 0.15, and 0.05 mM). This result is significant in view of the proposed biologically active model of oxytocin, in which the side chain of the 5 position residue was assigned to contain an "active element" responsible for the intrinsic activity of the hormone when bound to the uterine receptor.
D000818:Animals; D001216:Asparagine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002645:Chickens; D004231:Diuresis / Q000187:drug effects; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D010121:Oxytocin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D014590:Uterine Contraction / Q000187:drug effects
D010121:Oxytocin; D001216:Asparagine