Active-site studies of neurohypophyseal hormones: Synthesis and pharmacological properties of [5-(N4,N4-dimethylasparagine)]oxytocin

Article abstract of DOI:10.1021/jm00193a029

Synthesis and biological properties of [5 (N⁴, N⁴-demethylasparagine)] 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moiety in the side chain of the asparagine residue in position 5 of the posterior pituitary hormone oxytocin have been replaced by two methyl groups.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 possess 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.