The Synthesis and Pharmacological Study of 4-decarboxamido-oxytocin (4-alpha-aminobutyric Acid-oxytocin) and 5-decarboxamido-oxytocin (5-alanine-oxytocin).

Oxytocin, the main oxytocic-milk-ejecting-avian depressor principle of the posterior pituitary gland, the structure of which is shown in Fig. 1, possesses a number of chemical functional groups : a primary amino group in position 1, a phenolic hydroxyl group in position 2, three carboxamide groups in positions 4, 5, and 9, and a disulfide linkage in t.he 20.membered cyclic m0iet.y. The significance of t,he presence of t,hese functional groups to the possession of biological activity of the hormone has been investigated in this and other laborat.ories t.hrough the synthesis and study of various analogues of osytocin. The importance of the phenolic hydroxyl group and the primary amino group to the biological activity of oxytocin has already been examined by synthesis of analogues of the hormone lacking these groups, namely, deoxy-oxytocin (2-5), deamino-oxytocin (6, 7), and deamino-deoxy-osytocin @).I These st.udies showed that the phenolic hydroxyl group in osytocin is not essential for the production of the biological responses characberistic of the hormone, but its presence does contribute strongly to the avian depressor and oxyt,ocic potencies of oxytocin. Deamino-oxytocin, in which the free amino group is replaced by hydrogen, has very high avian depressor and oxytocic activities in comparison with oxytocin, and exhibits an ant,idiuretic activit.y approximately 5 times that of oxyt,ocin (6, 7). Thus the amino group of oxytocin is not required for the manifestation of biological activity. The act,ivities of deamino-deoxy-osytocin (8) are similar to those of deoxy-oxyt,ocin. When the disulfide linkage of oxytocin was replaced by hydrogens through the use of Raney nickel, the resulting dethiooxytocin was found to be devoid of avian depressor activity (9) and oxyt,ocic activit,y (IO). In a continuing effort, to probe the importance of the functional groups to the production of pharmacological properties of oxyto-