A Gly/Ala switch contributes to high affinity binding of benzoxazinone-based non-peptide oxytocin receptor antagonists.
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.
Hawtin
Stuart R
SR
School of Biosciences, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Ha
Sookhee N
SN
Pettibone
Douglas J
DJ
Wheatley
Mark
M
D000409:Alanine / Q000235:genetics; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D065092:Antidiuretic Hormone Receptor Antagonists; D048588:Benzoxazines; D001667:Binding, Competitive; D005998:Glycine / Q000235:genetics; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010078:Oxazines / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D017354:Point Mutation / Q000235:genetics; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D018045:Receptors, Oxytocin / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D017483:Receptors, Vasopressin / Q000235:genetics; D013329:Structure-Activity Relationship
D065092:Antidiuretic Hormone Receptor Antagonists; D048588:Benzoxazines; C096766:L 371257; C112585:L 372662; D008024:Ligands; D010078:Oxazines; D010880:Piperidines; D011725:Pyridines; D018045:Receptors, Oxytocin; D017483:Receptors, Vasopressin; D000409:Alanine; D005998:Glycine