A Highly Potent Analogue of Oxytocin, Desamino-oxytocin*T

The functional groups in the oxytocin molecule consist, from a chemical standpoint, of a primary amino, a phenolic hydroxyl, three carboxamide groups, and a disulfide linkage. Studies on the relation of structure to biological activity in this and other laboratories have been concerned in part with the significance of these functional groups to the production of a biological response at the site of action. Recently attention has been directed toward the synthesis of analogues of oxytocin which lack one or more of these functional groups. The importance of the phenolic hydroxyl group for the biological activity of oxytocin has already been assessed. This was made possible by the synthesis of 2-phenylalanine oxytocin (2, 3). This analogue, in which the tyrosine residue of oxytocin was replaced by phenylalanine, possesses uterine-contracting, avian depressor, and milk-ejecting activities. Although 2-phenylalanine oxytocin (desoxy-oxytocin) has only about one-eighth the avian depressor activity of oxytocin when assayed according to the United States Pharmacopeia (4), it is none the less a potent pharmacological agent. Thus, 0.033 mg of this compound has the same activity as 1 mg of the U.S.P. Standard Powder which in turn has the same activity as 0.004 mg of oxytocin. Even higher activities have been observed in assays employing rat and cat uteri in situ (5). Thus the phenolic hydroxyl group is not essential for biological activity but its presence does enhance the activity. The important point, however, is that in the absence of the phenolic group the biological effects are present to a considerable degree. In the present paper the synthesis and biological activities of desamino-oxytocin, an analogue lacking the free amino group present in oxytocin, are described. This study has afforded an opportunity of determining whether the presence of an amino group is vital to the possession of pharmacological activity. Desamino-oxytocin (1-P-mercaptopropionic acid oxytocin) (Fig. 1) differs from oxytocin at the 1 position, where the halfcystine residue bearing the free amino group is replaced by a &mercaptopropionic acid residue. The protected octapeptide, N-carbobenzoxy-O-benzyl-L-tyrosyl-Lisoleucyl-nglutaminyl-Lasparaginyl-Sbenzyl-ncysteinyln-prolyl-n-leucylglycinamide, was synthesized by the stepwise p-nitrophenyl ester procedure used earlier in this laboratory for the synthesis of oxytocin (6). Treatment of the resulting protected octapeptide with hydrogen bromide in acetic acid re-