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A Gly/Ala switch contributes to high affinity binding of benzoxazinone-based non-peptide oxytocin receptor antagonists
- Source :
- FEBS Letters; Jan2005, Vol. 579 Issue 2, p349-356, 8p
- Publication Year :
- 2005
-
Abstract
- 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<subscript>1a</subscript> vasopressin receptor. Examination of receptor sequences from different species identified Ala<superscript>318</superscript> 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<superscript>318</superscript> provides a direct hydrophobic contact with a methoxy group of L-371,257 and L-372,662. [Copyright &y& Elsevier]
- Subjects :
- PEPTIDES
OXYTOCIN
PHARMACOLOGY
VASOPRESSIN
Subjects
Details
- Language :
- English
- ISSN :
- 00145793
- Volume :
- 579
- Issue :
- 2
- Database :
- Complementary Index
- Journal :
- FEBS Letters
- Publication Type :
- Academic Journal
- Accession number :
- 16030758
- Full Text :
- https://doi.org/10.1016/j.febslet.2004.10.108