Nanomolar-affinity, non-peptide oxytocin receptor antagonists

J Med Chem. 1993 Dec 10;36(25):3993-4005. doi: 10.1021/jm00077a002.

Abstract

Non-peptide antagonists of the peptide hormone oxytocin (OT) with nanomolar OT receptor affinities are described. These compounds incorporate novel amido- and amidoalkylcamphor variations to the lead structure L-366,509 (1) to achieve receptor affinity enhancements of 2-3 orders of magnitude over that compound. The new OT antagonist L-367,773 (35) is shown to be an orally bioavailable agent with good duration in vivo and to inhibit OT-stimulated uterine contractions effectively in several in vitro and in vivo models.

MeSH terms

  • Animals
  • Binding Sites / drug effects
  • Female
  • Oxytocin / antagonists & inhibitors
  • Piperazines / chemical synthesis*
  • Piperazines / chemistry
  • Piperazines / pharmacology
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Rats
  • Receptors, Oxytocin / antagonists & inhibitors*
  • Receptors, Oxytocin / metabolism
  • Spiro Compounds / chemical synthesis*
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology*
  • Structure-Activity Relationship

Substances

  • Piperazines
  • Piperidines
  • Receptors, Oxytocin
  • Spiro Compounds
  • L 366509
  • Oxytocin