Analogues of a potent oxytocin antagonist having a ureido group in the amino acid side chain in position 4 or 5

摘要

Oxytocin(OT)antagonists of high potency and high specificity may be useful to determine the contribution of OT during labor or to inhibit preterm labor.The OT analogue(cyclo S~1-S~6)[(S)Pmp-D-Trp-Ile-Gln-Asn-Cys-Pro-Arg-Gly-NH_2],PA,in which(S)Pmp is beta,beta-(3-thiapentamethylene)-beta-mercaptopropionic acid,is a potent antagonist of OT uterotonic action.In preliminary studies,position 4 or position 5 of PA was substituted with Orn(Carb),in which Carb is carbamoyl.Encouraged by the results of the bioassays,we extended the study of carbamoyl substitution also to the highly potent OT antagonist(cyclo S~1-S~6)[(S)Pmp~1,D-Trp~2,Pen~6,Arg~8]OT,[Pen~6]PA,which inhibits labor in rats and baboons.Analogues of general formula(cyclo S~1-S~6)[(S)Pmp-D-Trp-Ile-X-Y-Z-Pro-Arg-Gly-NH_2],in which X or Y = Lys,Orn,Dab(1,4-L-diaminobutyric acid),Dap(1,3-L-diaminopropionic acid),and Z = Cys or Pen,were synthesized by SPPS,purified and characterized.Each of these analogues was carbamoylated by treatment with KCNO in DMF,yielding the corresponding X(Carb)or Y(Carb)derivative.We thus obtained two sets of analogues in which we graded the proximity of the ureido group to the peptide backbone.The potencies of these analogues were studied in the rat uterotonic in vitro assay,and for some of them also in the rat pressor and antidiuretic assays(Table 1).The antagonistic potency was expressed as pA_2.