4-β-Alanine-oxytocin: An Oxytocin Analog Containing a Twenty-one-membered Disulfide Ring^*

Abstract

4-/3-Alanine-oxytocin, an analog of oxytocin containing a /3-alanine residue in place of the glutamine residue in the 4 position in the hormone, has been synthesized and tested for various pharmacological activities in comparison with 4-glycine-oxytocin. Both of these analogs lack the carboxamide-containing side T A he synthesis of oxytocin (du Vigneaud et a/., 1953, 1954), the principal oxytocic and milk-ejecting hormone of the posterior pituitary gland, has provided a means of studying the relationship of chemical structure to biological activity in this octapeptide hormone, the structure of which is shown in Figure 1.Efforts to elucidate this relationship in this and other laboratories during the past decade have centered on the total synthesis of numerous analogs of the hormone, incorporating various modifications of its structure, and the comparison of the pharmacological properties of these synthetic analogs with those of oxytocin. Along with some other aspects of the general problem, the studies in our laboratory have been focused particularly on the importance of the presence of the individual chemical functional groups, the specificity of the 20membered disulfide ring, and the relation of the stereostructure of the seven optically active amino acid residues to the pharmacological manifestations of oxytocin.Recently Drabarek (1964) in this laboratory synthesized three analogs of oxytocin in which the tyrosine, isoleucine, and glutamine residues in positions 2, 3, and 4 were replaced, respectively, by a glycine residue. The only one of these compounds that showed pharmacological activity was 4-glycine-oxytocin, which possessed 5.5 units/mg of oxytocic activity, 17 units/mg of

Synthesis and some pharmacological properties of five analogs of oxytocin having L-homocysteine in position 6

“…methylene group at position 6. We report here the synthesis of five analogs of oxytocin in which the Cys6 residue has been replaced by an L-homocysteine residue. Combining this modification with various residues in position 1, the following analogs of oxytocin have been prepared: [6-homocysteine]oxytocin (3)16 ([Hey6]oxytocin), [1,6-homocystine]oxytocin (5) ]oxytocin), [1-amercaptoacetic acid,6-homocysteine]oxytocin (7)16 ([«-Maa1,Hey6]oxytocin), [ -ß-mercaptopropionic acid,6homocysteine]oxytocin (9) ([d-Mpa1,Hcy6]oxytocin), and [l-7-mercaptobutyric acid,6-homocysteine]oxytocin (11) ( lO'7 (8), V= 0.4 X lO-7, 2 = 6.74 M= 4.6 X 10"' (12), T= 1.5 x 10-', pA, = 7.34 M= 6.8 X 10"6 (7), T= 1.4 X 10"6, 2 = 5.17…”

“…The analogs were purified by partition chromatography20 and gel filtration.21 During the purification of compounds 7, 9, and 11, a by-product was isolated in the gel filtration step. In one case (9) the amino acid analysis of the by-product contained Tyr, lie, Asp, Glu, and NH3 in the ratio of 1:1:1:1:2 as the only identifiable components (see Experimental Section). This result would seem to indicate that the Hcy-Pro bond was easily cleaved by the Na-NHs treatment.…”

Bradykinin analogs containing .beta.-homoamino acids

“…(1) methylene chloride wash (4 X 50 ml); (2) ethanol wash (4X5 ml); (3) acetic acid wash (4 X 50 ml); (4) 1 N HCl in AcOH wash (1 X 50 ml); (5) 1 N HCl in AcOH treatment (1 X 50 ml, 25 min); (6) acetic acid wash (4 X 50 ml); (7) ethanol wash (4 X 50 ml); (8) methylene chloride wash (4 X 50 ml); ( 9) triethylamine wash (6.5% in methylene chloride, 2 X 50 ml, 5 min); (10) methylene chloride wash (4 X 50 ml). ( 11) A solution of (3S)-3-tert-butyloxycarbonylamino-4-phenylbutyric acid (2.1 g, 7.5 mmol) in methylene chloride (35 ml) was added followed, after 25 min, by the addition of a solution of dicyclohexylcarbodiimide (1.55 g, 7.5 mmol) in methylene chloride (2.5 ml).…”

β-Peptide foldamer helices with tailored diameters

“…130,131,137 Many instances exist in the literature for this peptidomimetic approach, such as structurally modified angiotensin-II 138 and gastrin agonists, 139 an oxytocin-analogue peptide 140 or bombesin receptor antagonists. 141,142 Incorporation of cyclic β-amino residues into endomorphine-2 is also available.…”