[1-Deaminopenicillamine,4-threonine]oxytocin, a potent inhibitor of oxytocin

Abstract

[1-Deaminopenicillamine,4-threonine]oxytocin was prepared in duplicate from S-benzyl-3-mercapto-3,3-dimethylpropanoyl-Tyr(Bzl)-Ile-Thr(Bzl)-Asn-Cys(Bzl)-Pro-Leu-Gly-NH2 (I) by removal of the Bzl-protecting groups with Na-NH3, followed by cyclization of the resulting disulfhydryl compound with K3Fe(CN)6. The analogue was purified by desalting on Sephadex G-15 in 50% acetic acid and gel filtration on Sephadex G-15. The protected peptide I was synthesized by the solid-phase method and by a combination of solid-phase synthesis and an [8 + 1] coupling in solution. The analogue has no detectable agonist activity in rat vasopressor or isolated rat uterus assays. It has an antivasopressor pA2 [negative log of the concentration of antagonist that reduces the effect of a double dose of agonist to that of a single dose] of 6.67 .+-. 0.09. It is a potent inhibitor of the in vitro oxytocic response tp oxytocin and has a pA2 value of 7.46 .+-. 0.04. (Material from the repeat synthesis has a pA2 value of 7.59 .+-. 0.08). Thus the substitution of threonine for glutamine in the antagonist [1-deaminopenicillamine]oxytocin (pA2, 7.14 .+-. 0.05) has effected a 2-fold increase in inhibitory potency. [1-Deaminopenicillamine,4-threonine]oxytocin is 1 of the most potent inhibitors of oxytocin known to date.