[1-Penicillamine,2-leucine]oxytocin. Synthesis and pharmacological and conformational studies of a potent peptide hormone inhibitor

Abstract

[1-Penicillamine,2-Leu]oxytocin was synthesized by the solid-phase method of peptide synthesis and purified by partition chromatography on Sephadex G-25, followed by gel filtration. The peptide was a very potent competitive inhibitor of oxytocin in the oxytocic assay with a pA2 [effective concentration of agonist to antagonist] of 7.14 and an inhibitor of oxytocin in the milk-ejecting assay. The compound showed no agonist activity in either of these assays. Its inhibitory activity at the uterus was of prolonged duration. The 13C nuclear magnetic resonance spectral properties and the 13C T1 (spin-lattice) relaxation times of [Pen1,Leu2]oxytocin were determined. The results were compared with previous studies of [Pen1]oxytocin, a related competitive inhibitor and oxytocin, the native hormone agonist. The hormone inhibitors [Pen1,Leu2]oxytocin and [Pen1]oxytocin have similar conformational and dynamic properties different than those of the agonist, oxytocin.