title: Synthetic antagonists of the myometrial response to vasopressin and oxytocin.
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 (pA2) was between 7.6 and 8.9 for all the new inhibitors compared with 7.2 for d(OEt)-oxytocin. The highest pA2 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-Thr-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.(ABSTRACT TRUNCATED AT 250 WORDS)
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003864:Depression, Chemical; D004231:Diuresis / Q000187:drug effects; D005260:Female; D006728:Hormones / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D009215:Myometrium / Q000187:drug effects*; D010121:Oxytocin / Q000031:analogs & derivatives* / Q000494:pharmacology; D011247:Pregnancy; D051381:Rats; D014590:Uterine Contraction / Q000187:drug effects*; D014667:Vasopressins / Q000494:pharmacology
chemical_list: D006728:Hormones; D014667:Vasopressins; C004748:deaminooxytocin; D010121:Oxytocin