A Gly/Ala switch contributes to high affinity binding of benzoxazinone-based non-peptide oxytocin receptor antagonists

Stuart R. Hawtin, Sookhee N. Ha, Douglas J. Pettibone, Mark Wheatley

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Non-peptide antagonists of the oxytocin receptor (OTR) have been developed to prevent pre-term labour. The benzoxazinone-based antagonists L-371,257 and L-372,662 display pronounced species-dependent pharmacology with respect to selectivity for the OTR over the V 1a vasopressin receptor. Examination of receptor sequences from different species identified Ala 318 in helix 7 of the human OTR as a candidate discriminator required for high affinity binding. The mutant receptor [A318G]OTR was engineered and characterised using ligands representing many different chemical classes. Of all the ligands investigated, only the benzoxazinone-based antagonists had decreased affinity for [A318G]OTR. Molecular modelling revealed that Ala 318 provides a direct hydrophobic contact with a methoxy group of L-371,257 and L-372,662.

Original languageEnglish
Pages (from-to)349-356
Number of pages8
JournalFEBS Letters
Volume579
Issue number2
DOIs
Publication statusPublished - 17 Jan 2005
Externally publishedYes

Bibliographical note

Free access

Keywords

  • GPCR
  • Ligand binding
  • Non-peptide antagonist
  • Oxytocin receptor

ASJC Scopus subject areas

  • Biophysics
  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology

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