Analogues of oxytocin antagonists bearing a ureido group in the amino acid side chain at position 4 or 5.

Substitution of the side chain carboxamido group at position 4 in the potent oxytocin antagonist (OTA) [ThiaPmp(1), D-Trp(2), Cys(6), Arg(8)]-OT, PA, in which ThiaPmp = beta,beta-(3-thiapentamethylene)-beta-mercaptopropionic acid, led to [Orn(Car)(4)]-PA, ([Cit(4)]-PA), which had uterotonic antagonistic activity equal to that of PA. The same modification at position 5, leading to [Cit(5)]-PA, resulted in antagonistic potency more than 10 times lower than that of PA. This paper also describes the same substitutions introduced in the highly potent OTA [Pen(6)]-PA (antioxytocic in vitro pA(2) = 8.72). Analogues of the general formula [U(4)-X(5)-Pen(6)]-PA, in which U = Lys, Orn, Dab, Dap or X = Orn, Dab or Dap, were synthesized by SPPS. Each of these analogues was carbamoylated by treatment with KCNO in DMF-H(2)O, yielding the corresponding U(Car)(4) or X(Car)(5) derivatives. In the uterotonic assay, the substitution with the ureido group at Gln(4) results in retention of high antagonistic potency, albeit somewhat lower than that of PA, e.g. [Orn(Car)(4), Pen(6)]-PA and [Dab(Car)(4), Pen(6)]-PA having pA(2) = 8.52 and pA(2) = 8.42 respectively. In the pressor assay, [Lys(Car)(4), Pen(6)]-PA and [Dab(Car)(4), Pen(6)]-PA were somewhat weaker antagonists of arginine vasopressin than [Pen(6)]-PA; [Dap(Car)(4), Pen(6)]-PA showed only a faint trace of pressor agonistic activity. The substitution with the ureido group at position 5 leads to a significant loss of OTA potency in the in vitro uterotonic assay. The [Orn(Car)(5), Pen(6)]-PA was the most potent of the series (pA(2) = 8.05). An interesting finding is that [Dap(Car)(5), Pen(6)]-PA is equipotent with its precursor [Dap(5), Pen(6)]-PA (potency in the uterotonic test in vitro, pA(2) = 7.71 and pA(2) = 7.68, respectively). Furthermore, neither [Dap(5), Pen(6)]-PA nor [Dap(5), Pen(6), Gly(9)]-PA exhibited activity in the antidiuretic or pressor assays. Although these last two analogues show some decrease in antioxytocin potency, they behave as pure oxytocin antagonists, which makes them attractive candidates for further studies on the development of potent and specific OTAs. Copyright (c) 2005 European Peptide Society and John Wiley & Sons, Ltd.