Synthesis and some pharmacological properties of [4-threonine,7-glycine]oxytocin, [1-(L-2-hydroxy-3-mercaptopropanoic acid),4-threonine,7-glycine]oxytocin (hydroxy[thr4, gly7]oxytocin), and [7-glycine]oxytocin, peptides with high oxytocic-antidiuretic selectivity

• Published in: Journal of medicinal chemistry 1977-01, Vol.20 (1), p.120-123
• Main Authors: Lowbridge, John, Manning, Maurice, Haldar, Jaya, Sawyer, Wilbur H
• Format: Article
• Language: English
• Subjects: Amino Acids, Sulfur - chemical synthesis; Glycine; Humans; Hydroxylation; Methods; Oligopeptides - chemical synthesis; Oxytocin - analogs & derivatives; Oxytocin - chemical synthesis; Threonine; Tiopronin - chemical synthesis; Vasopressins - chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00211a025

[4-Threonine, 7-glycine]oxytocin and [1-(L-2-hydroxy-3-mercaptopropanoic acid), 4-threonine, 7-glycine]oxytocin (hydroxy[Thr4, Gly7]oxytocin) were synthesized by a combination of solid-phase and classical methods of peptide synthesis. A protected octapeptide was synthesized by the solid-phase method and following ammonolysis and purification 1 + 8 couplings in solution were employed to furnish the required key nonapeptide and acyl octapeptide intermediates, respectively. [7-Glycine]oxytocin was prepared from a sample of the protected nonapeptide intermediate used in the original synthesis of this peptide. [7-Glycine]oxytocin has an oxytocic potency (O) of 93 +/- 4 units/mg and an antidiuretic potency (A) of 0.0056 +/- 0.0003 units/mg. It has an O/A ratio of 16 000. [4-Threonine, 7-glycine]oxytocin has an oxytocic potency of 166 +/- 4 units/mg and an antidiuretic potency of 0.002 +/- 0.0004 units/mg. Its O/A ratio is 83 000. Threonine substitution has thus brought about a substantial enhancement in oxytocic activity and a fivefold enhancement in O/A selectivity. Hydroxy [Thr4, Gly7]oxytocin has an oxytocic potency of 218 +/- 8 units/mg and antidiuretic potency of 0.0040 +/- 0.0005 units/mg. Its O/A ratio is thus 54 500. All three 7-glycine-substituted analogues exhibit a marked sensitivity to Mg2+ on the rat uterus assay ststem and in the presence of 0.5 mM Mg2+ had oxytocic potencies in the range of 900-1000 units/mg. Should these peptides exhibit enhanced oxytocic selectivity in humans, they might offer a greater margin of safety than oxytocin in those clinical stiuations in which the latter is currently employed.