2. Academic Validation
  3. A Gly/Ala switch contributes to high affinity binding of benzoxazinone-based non-peptide oxytocin receptor antagonists

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

  • FEBS Lett. 2005 Jan 17;579(2):349-56. doi: 10.1016/j.febslet.2004.10.108.
Stuart R Hawtin 1,  Sookhee N Ha,  Douglas J Pettibone,  Mark Wheatley
Affiliations

Affiliation

  • 1 School of Biosciences, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
PMID: 15642343 DOI: 10.1016/j.febslet.2004.10.108
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.

Figures
Products