Some pharmacological properties of a synthetic oxytocin analogue [1-N-carbamoyl-hemicystine-2-O-methyltyrosine]-oxytocin (carbamoyl-methyloxytocin), an antagonist to the neurohypophysial hormones.

1. A synthetic oxytocin analogue, [1-N-carbamoyl-hemicystine-2-O-methyltyrosine]-oxytocin (carbamoyl-methyloxytocin), has been tested as an antagonist to the actions of oxytocin and vasopressin on the uterus, the mammary gland and blood pressure.2. The analogue inhibited the response of the isolated rat uterus to both oxytocin and vasopressin without itself stimulating the uterus to contract. The responses to equipotent doses of oxytocin and vasopressin were inhibited equally. There was little or no inhibition of the response to bradykinin. carbachol, angiotensin or 5-hydroxytryptamine with doses of the analogue up to 160 times that required to inhibit the response to oxytocin by 50%. The analogue caused a parallel displacement of the log dose-response curve for oxytocin; the pA(2) value (2 min contact) varied from 6.4 to 7.1 according to the ionic composition of the solution in the organ bath.3. The analogue inhibited the response of the rat uterus in situ to oxytocin but not to angiotensin or 5-hydroxytryptamine. It did not stimulate the uterus.4. When, in certain experimental conditions, spontaneous activity occurred in the isolated uterus or the uterus in situ, this activity was unaffected by the analogue but the increase in amplitude and frequency of contractions caused by oxytocin was inhibited. The regular rhythm of contractions induced in the quiescent uterus by the intravenous infusion of oxytocin was interrupted by intravenous injections of the analogue.5. The response of the isolated strip of rat mammary gland to the analogue depended on whether or not magnesium was present in the bath solution. In the presence of this ion, the analogue generally caused an increase in tension; in its absence, it acted as a pure antagonist. As on the isolated uterus, oxytocin and vasopressin were equally inhibited, and the analogue caused a parallel displacement of the log dose-response curve for oxytocin. With 0.9 mM Ca and 1.0 mM Mg, the mean pA(2) value (2 min contact) was 6.28 +/- 0.08 (S.E.)6. In the lactating rat, the analogue inhibited the milk-ejection response to oxytocin and vasopressin but not that to acetylcholine, bradykinin or 5-hydroxytryptamine. A milk-ejection response to the analogue itself was seen occasionally with retrograde arterial but not with intravenous injections.7. The analogue inhibited the avian depressor response to oxytocin and the rat pressor response to vasopressin.8. On all assay preparations, the degree of inhibition caused by the analogue was dependent on the dose, and the inhibition could be surmounted by increasing the dose of agonist. Recovery usually occurred within 15 min. These features, together with the parallel displacement of the dose-response curve for oxytocin on the isolated uterus and mammary strip, and the equal inhibition of the responses to oxytocin and vasopressin, suggest that carbamoyl-methyl-oxytocin acts as a specific competitive inhibitor of the neurohypophysial hormones.9. The structure-activity relationships of analogues of oxytocin having substituents in the terminal amino and phenolic hydroxyl groups, and some practical applications of the carbamoyl-methyl analogue, are discussed.