Solid-Phase Synthesis of [2-Isoleucine,4-leucine]oxytocin and [2-Phenylalanine,4-leucine] oxytocin and Some of Their Pharmacological Properties

Victor J. Hruby, Fugen Mustio, Charles M. Groginsky, Peter M. Gitu, Don Saba, Walter Y. Chan

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

[Ile2,Leu4]oxytocinand [Phe2,Leu4]oxytocin have been synthesized using the solid-phase method. In the synthesis of [Phe2,Leu4]oxytocin a benzhydrylamine resin support was used, and a diphenylmethyl carboxamide protecting group was used for the asparagine residue. The protected asparagine residue was coupled to the peptide resin with dicyclohexylcarbodiimide. The peptide was cleaved from the resin and the diphenylmethyl carboxamide and 5-p-methoxybenzyl protecting groups weee removed by HF(l). The disulfhydryl peptide was oxidized and purified to give the desired cyclic peptide. In the synthesis of [lie 2,Leu4]oxytocin, terf-butyloxycarbonylasparagine was coupled to the peptide resin with dicyclohexylcarbodiimide and 1-hydroxybenzotriazole. No cyano formation was detected. [Ile2,Leu4]oxytocin and [Phe2,Leu4]oxytocin weee found to possess weak pressor activities and no antidiuretic activities. [lie2,Leu4]-oxytocin had a mild natriuretic-diuretic activity whereas [Phe2,Leu4]oxytocin had only a weak natriuretic activity. Neither compound had a detectable oxytocic activity when assayed in the isolated uterus in a Mg2+-free van Dyke-Hastings solution. On the contrary, they inhibited the oxytocic response of oxytocin in this in vitro system. Their oxytocic inhibitory activity was found to be dependent on Ca2+ concentration. When the Ca2+ concentration in the bathing medium was increased from 0.5 to 1.0 mM/1., the inhibitory activity of [Phe2,Leu4] oxytocin was markedly reduced while [Ile2,Leu4]oxytocin became a weak agonist.

Original languageEnglish (US)
Pages (from-to)624-629
Number of pages6
JournalJournal of Medicinal Chemistry
Volume16
Issue number6
DOIs
StatePublished - Jun 1 1973

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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