Targeting the prostaglandin F2α receptor for preventing preterm labor with azapeptide tocolytics

J Med Chem. 2011 Sep 8;54(17):6085-97. doi: 10.1021/jm200608k. Epub 2011 Aug 9.

Abstract

The prostaglandin-F2α (PGF2α) receptor (FP) was targeted to develop tocolytic agents for inhibiting preterm labor. Azabicycloalkane and azapeptide mimics 2-10 were synthesized based on the (3S,6S,9S)-indolizidin-2-one amino acid analogue PDC113.824 (1), which was shown to modulate FP by a biased allosteric mechanism, involving both Gαq- and Gα12-mediated signaling pathways, and exhibited significant tocolytic activity delaying preterm labor in a mouse model ( Goupil ; et al. J. Biol. Chem. 2010 , 285 , 25624 - 25636 ). Although changes in azabicycloalkane stereochemistry and ring size caused loss of activity, replacement of the indolizidin-2-one amino acid with azaGly-Pro and azaPhe-Pro gave azapeptides 6 and 8, which reduced PGF2α-induced myometrial contractions, potentiated the effect of PGF2α on Gαq-mediated ERK1/2 activation, and inhibited FP modulation of cell ruffling, a response dependent on the Gα12/RhoA/ROCK signaling pathway. Revealing complementarities of azabicycloalkane and azapeptide mimics, novel probes, and efficient tocolytic agents were made to study allosteric modulation of the FP receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aza Compounds / chemical synthesis
  • Aza Compounds / chemistry
  • Aza Compounds / pharmacology*
  • Blotting, Western
  • Cells, Cultured
  • Dinoprost / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Humans
  • Infant, Newborn
  • Kidney / cytology
  • Kidney / drug effects
  • Kidney / metabolism
  • Mice
  • Obstetric Labor, Premature / prevention & control*
  • Peptide Fragments / chemical synthesis
  • Peptide Fragments / chemistry
  • Peptide Fragments / pharmacology*
  • Pregnancy
  • Pregnancy, Animal / drug effects
  • Receptors, Prostaglandin / metabolism*
  • Signal Transduction / drug effects*
  • Tocolytic Agents / chemical synthesis
  • Tocolytic Agents / chemistry
  • Tocolytic Agents / pharmacology*
  • Uterine Contraction / drug effects*
  • rho-Associated Kinases / metabolism

Substances

  • Aza Compounds
  • Peptide Fragments
  • Receptors, Prostaglandin
  • Tocolytic Agents
  • prostaglandin F2alpha receptor
  • Dinoprost
  • rho-Associated Kinases
  • Extracellular Signal-Regulated MAP Kinases