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 language | English |
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Pages (from-to) | 349-356 |
Number of pages | 8 |
Journal | FEBS Letters |
Volume | 579 |
Issue number | 2 |
DOIs | |
Publication status | Published - 17 Jan 2005 |
Keywords
- non-peptide antagonist
- ligand binding
- oxytocin receptor
- GPCR