Bicyclization of a Weak Oxytocin Agonist Produces a Highly Potent Oxytocin Antagonist

Patricia S. Hill, D. David Smith, Victor J. Hruby, Patricia S. Hill, Jirina Slaninova

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

[Mpa1, Glu4, Cys6, Lys8]oxytocin was prepared and found to be a very weak agonist in the oxytocic assay with about 1/1400 the potency of the native hormone. Bicyclization of this compound via a lactam bridge between the Glu4 δ-carboxyl group and the ϵ-amino group of Lys8 led to the bicyclic analogue 4,8-cyclo[Mpa1, Glu4, Cys6, Lys8]oxytocin. This bicyclic peptide acts as a very potent antagonist of oxytocin in the rat uterus assay with an in vitro pA2 value of 8.2. In the in vivo oxytocic assay the pA2 value was 6.45. The peptide displays mixed agonist/antagonist character in the in vivo galactogogic assay. The implications of these results to hormone agonist and antagonist activity are discussed with respect to earlier studies on constrained oxytocin antagonists and the results from the X-ray crystal structure of deaminooxytocin.

Original languageEnglish (US)
Pages (from-to)3110-3113
Number of pages4
JournalJournal of the American Chemical Society
Volume112
Issue number8
DOIs
StatePublished - Jan 1990

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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