Synthetic antagonists of the myometrial response to vasopressin and oxytocin

Abstract

ABSTRACT With the aim of developing inhibitors of vasopressin-and oxytocin-induced uterine activity, 17 analogues of 1-deamino-oxytocin were synthesized by the solid-phase method. Modifications were made at positions 2, O-methyltyrosine (Tyr(OMe)) and O-ethyltyrosine (Tyr(OEt)), d -Tyr, d -Tyr(OEt), d -Trp; 4, Val,Thr and 8, Orn,Cit,Arg, d -Arg. The analogues were tested for antiuterotonic activity in vitro and in vivo in the rat and in vitro on myometrial strips from non-pregnant women and pregnant women at term. Their selectivity was also investigated in blood pressure and antidiuretic bioassays in rats. Results were compared with those from an original antiuterotonic analogue 1-deamino-2-Tyr(OEt)-oxytocin (d(OEt)-oxytocin). In the rat in vitro and in vivo all analogues possessed higher antiuterotonic activity than d(OEt)-oxytocin. The negative logarithm of the molar concentration of the antagonist which reduced the effect of a dose of agonist to that of half the dose (pA 2 ) was between 7·6 and 8·9 for all the new inhibitors compared with 7·2 for d(OEt)-oxytocin. The highest pA 2 value was found for 1-deamino-2-Tyr(OMe)-8-Orn-oxytocin (8·9 ± 0·2, s.e.m. ) and 1-deamino-2-Tyr(OEt)-4-Thr-8-Orn-oxytocin (8·9 ± 0·6). In myometrium from non-pregnant women the most potent peptide was 1-deamino-2- d -Tyr(OEt)-4-Th r-8-Orn-oxytocin (17·2 ± 2·0 times more potent that d(OEt)-oxytocin). In myometrium from pregnant women the inhibitory effects of the majority of the analogues were less pronounced. In the rat in vivo the most potent analogue 1-deamino-2- d -Trp-4-Val-8-Orn-oxytocin was 19·9 ± 2·5 times more active than d(OEt)-oxytocin. Exchanging l -tyrosine for the d form generally increased inhibitory activity as well as specificity of the analogues. Alkylation of the d -tyrosine residue did not appear to be necessary for inhibition. Substitution with d -tryptophan at position 2 gave analogues with high inhibitory potency in the rat in vitro and in vivo , but which exhibited weak effects in women in vitro. There was no correlation between the inhibitory effects on myometrium from non-pregnant and pregnant women nor between rat and human data. The high antiuterotonic activity of 1-deamino-2- d -Tyr(OEt)-4-Val-8-Orn-oxytocin and 1-deamino-2- d -Tyr(OEt)-4-Thr-8-Orn-oxytocin combined with low blood pressure and antidiuretic effects make these two analogues interesting for clinical studies. J. Endocr. (1986) 111, 125–131