The design of effective in vivo antagonists of rat uterus and milk ejection responses to oxytocin.

Several new synthetic analogs of the oxytocin antagonist [1-deaminopenicillamine]oxytocin have been prepared and tested for their abilities to inhibit responses to oxytocin by the isolated rat uterus in the absence and presence of Mg++, by the rat uterus in situ, and by the rat mammary gland in situ. Substituting 2-O-methyltyrosine in [1-deaminopenicillamine]oxytocin strikingly enhances antagonism of all uterin responses, and [1-deaminopenicillamine, 2-O-methyltyrosine]oxytocin and its 4-threonine analog are also potent inhibitors of the milk ejection response. Substituting 2-phenylalanine in [1-deaminopenicillamine]oxytocin also enhances antagonistic activities in all uterine assays, but [1-deaminopenicillamine, 2-phenylalanine]oxytocin retains agonistic activity on milk ejection assays. From these studies we can conclude that changes in the 1-position (1-deaminopenicillamine substitution) and the 2-position (2-O-methyltyrosine or 2-phenylalanine substitution) can have additive effects on antagonistic activities. Substitution of an 8-ornithine also enhances inhibitory potency in vivo, and this effect may also be additive to those of the substitutions in 1- and 2-positions. These findings provide many clues that may lead to the design of even more effective antagonists; several of the analogs reported here appear to the most effective antagonists of oxytocin in vivo yet reported and may be useful agents in further studies on the physiological functions of endogenous oxytocin.