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

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Abstract
[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 in rat assay systems. Its O/A ratio is 83,000. Threonine substitution has thus brought about a substantial enhancement in oxytocic activity and 5-fold 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 system 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 situations in which the latter is currently employed.