Antagonists of oxytocin featuring replacement with modified β-mercaptopropionic acids at position 1

Twenty analogues were synthesized of [Pmp¹, D-Trp², Arg⁸]oxytocin, PA, (Pmp = β,β-pentamethylene-β-mercaptopropionic acid), a potent antagonist of the uterotonic effect of oxytocin in the rat (uterotonic test in vitro, pA₂ = 7.77) and in the baboon. Systematic substitution of Pmp¹ was made with β-mercaptopropionic acids featuring replacement of the 4-methylene group of the cyclohexyl ring of Pmp with isosteric O, S, NH or with C = O. Since the more hydrophilic NH and C = O substitutions showed a sharply decreased antagonistic potency (rat uterotonic test in vitro), additional modifications were made to reduce their hydrophilicity. Acylation of the NH group with various acyl groups, and ketalization or thioketalization of C = O with more or less bulky substituents led to a partial restoration of potency, the N-carbamyl- and the 2-mercapto-2-adamantaneacetyl analogues being equipotent with PA. Internal cyclization by amidation of the NH-group with Gly-9, resulted in a bicyclic analogue, (cyclo 1-9)[(HN)Pmp¹, Gly⁹]PA which was equipotent with PA. When Pen-6 was introduced into the bicyclic derivative instead of Cys-6, to reduce the flexibility of the rings, the resulting (cyclo 1-9)[(HN)Pmp¹, Pen⁶, Gly⁹]PA had somewhat better potency (pA₂ = 8.17) in the uterotonic test and no detectable activity in the antidiuretic assay. In the case of substitution of PA with β, β-(3-thiapentamethylene)-β-mercaptopropionic acid, (S)Pmp, there was also an increase in inhibitory potency in the uterotonic test (pA₂ = 8.08); the analogue had extremely weak antidiuretic activity. To establish the importance of the steric effects of the Pen-6 substitution, analogues [Pen⁶]PA and [(S)Pmp¹, Pen⁶]PA were made and found to be very potent, with a pA₂ of 8.72 and 8.86, respectively. The high potency of the latter analogue and its extremely weak action in the diuretic assay makes it an attractive candidate for studies on the inhibition of the biological effects of oxytocin and for the prevention of preterm labour.