Synthesis of Desamino-desoxy-oxytocin, a Biologically Active Analogue of Oxytocin*

In the study of the relationship between structure and biological activity in the neurohypophysial hormones, oxytocin and vasopressin, attention has recently been focused in this and other laboratories on the chemical functional groups. Aside from peptide linkages, these chemical functional groups in oxytocin consist of a primary amino, a phenolic hydroxyl, three carboxamide groups, and a disulfide linkage. The importance of the phenolic hydroxyl group and the primary amino group to the biological activity of oxytocin has already been investigated through the preparation and study of various derivatives of oxytocin in which one of these functional groups is blocked by a substituent and through the synthesis and study of two analogues of the hormone, one lacking the phenolic group (desoxy-oxytocin) (l-4) and the other lacking the amino group (desamino-oxytocin) (576). Desoxy-oxytocin (2-phenylalanine-oxytocin) possesses approximately one-sixteenth of the oxytocic activity of oxytocin and approximately one-eighth of its avian depressor activity (1, 2). When the oxytocic activity is determined on the cat uterus in situ, the desoxy analogue is approximately one-third as active as oxytocin (2). The rat pressor activity of desoxyoxytocin is approximately one-tenth that of oxytocin and the antidiuretic activity is also very low (3,4). It may be concluded from these data that the phenolic hydroxyl group in oxytocin is not essential for the production of the biological responses characteristic of oxytocin, but the presence of the phenolic group greatly enhances these activities. Although desoxy-oxytocin is less active than oxytocin, it is a highly potent pharmacological agent with respect to certain activities of the hormone when one considers the amount of compound necessary to produce an effect. On the other hand, the blocking of the phenolic hydroxyl group of oxytocin by a methyl group through total synthesis of Omethyl-oxytocin from 0-methyltyrosine (7, 8) leads to an analogue which possesses approximately one-tenth of the avian depressor activity exhibited by desosy-oxytocin (7). Furthermore, the 0-methyl-oxytocin has some inhibitory effect on the pressor response of arginine-vasopressin (7) and a marked inhibitory effect on the oxytocic response of oxytocin on the isolated rat uterus (8, 9). Thus the effects of blocking the phenolic hydroxy group of oxytocin with a methyl group differ considerably from those of eliminating the group entirely. This divergence in results, depending upon whether the functional group has been eliminated entirely or blocked with a substituent, may