Combined high oxytocic with negligible antidiuretic and pressor activities in multisubstituted oxytocins

Abstract

Oxytocin analogues which combine high oxytocic activities with negligible antidiuretic and pressor activities have been studied. [4-Threonine,7-glycine]oxytocin, [1-(L-2-hydroxy-3-mercaptopropionic acid),4-threonine,7-glycine]oxytocin, and [1-(L-2-hydroxy-3-mercaptopropionic acid)]oxytocin were found to possess the following specific biological activities respectively: rat uterotonic, 270 +/- 10, 337 +/- 23, 1542 +/- 0.4; rat antidiuretic, 0.002 +/- 0.0008, 0.048 +/- 0.005, 40.3 +/- 2.4. The results are analyzed from a conformation-activity viewpoint in a continued attempt to evaluate the scope and limitations of this approach in comparison to structure-activity studies.

Hydroxy Analogues of Oxytocin and of Lysine‐vasopressin

“…Hope & Walti (1974) first reported the relatively high pressor potency of [L-Hmp'] oxytocin which they found to be 10 times that of oxytocin (Table 1). Stahl & Walter (1977) confirmed this finding, and found that the antidiuretic activity was equally high. Manning et al (1976) also found that the pressor and antidiuretic activities were approximately equal but only 5 times those of oxytocin.…”

“…This disproportionately high activity appears to result from the absence of Mg2+ from the Munsick's solution in the bath fluid. Other workers using the same experimental conditions have obtained a potency of 1607 u/mg (Hope & Wiilti, 1971;Walti & Hope, 1972): 1275 u/mg (Manning et al, 1976) and 1542 u/mg (Stahl & Walter, 1977). However, for the rat isolated uterus in the presence of 0.5 M Mg2", Manning et al (1976) obtained a potency of 868 u/mg: this is close to the potency which we obtained on the rat uterus in situ and on the rat mammary gland both isolated and in situ.…”

“…In the presence of Mg2 , either in the organ bath or in vivo, their potency in relation to oxytocin would be reduced and, in its absence, enhanced. It is more difficult to account for the exceptionally high avian depressor activity of [L-Hmp'] oxytocin reported by Stahl & Walter (1977). Although too little of the antagonist, N-carbamoyl-0-methyl oxytocin, was available to determine pA2 values (Arunlakshana & Schild, 1959), the experiment illustrated in Figure 1 provides some evidence that [L-Hmp'] oxytocin acts on the same tissue receptor as oxytocin on the isolated uterus.…”

“…The results are described in this paper. Since this work was carried out [L-Hmp'] oxytocin has been synthesized by two other groups (Manning, Lowbridge, Haldar & Sawyer, 1976;Stahl & Walter, 1977) in the course of their studies of structure-activity relationships and a wide spectrum of pharmacological activities has now been described for this analogue.…”