Targeting the Prostaglandin F2α Receptor for Preventing Preterm Labor with Azapeptide Tocolytics.
Summary of "Targeting the Prostaglandin F2α Receptor for Preventing Preterm Labor with Azapeptide Tocolytics."
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.
Department of Medicine, McGill University Health Center Research Institute , Montréal H3A 1A1, Québec, Canada.
This article was published in the following journal.
Name: Journal of medicinal chemistry
Medical and Biotech [MESH] Definitions
Cell surface receptors that bind prostaglandins with high affinity and trigger intracellular changes which influence the behavior of cells. Prostaglandin receptor subtypes have been tentatively named according to their relative affinities for the endogenous prostaglandins. They include those which prefer prostaglandin D2 (DP receptors), prostaglandin E2 (EP1, EP2, and EP3 receptors), prostaglandin F2-alpha (FP receptors), and prostacyclin (IP receptors).
Drugs that prevent preterm labor and immature birth by suppressing uterine contractions (TOCOLYSIS). Agents used to delay premature uterine activity include magnesium sulfate, beta-mimetics, oxytocin antagonists, calcium channel inhibitors, and adrenergic beta-receptor agonists. The use of intravenous alcohol as a tocolytic is now obsolete.
Fetal Membranes, Premature Rupture
Spontaneous tearing of the membranes surrounding the FETUS any time before the onset of OBSTETRIC LABOR. Preterm PROM is membrane rupture before 37 weeks of GESTATION.
Receptors, Prostaglandin E, Ep4 Subtype
A subtype of prostaglandin E receptors that specifically couples to GS ALPHA GTP-BINDING PROTEIN SUBUNITS and subsequently activates ADENYLATE CYCLASE. The receptor may also signal through the activation of PHOSPHATIDYLINOSITOL 3-KINASE.
Receptors, Prostaglandin E, Ep1 Subtype
A subtype of prostaglandin E receptors that specifically couples to GTP-BINDING PROTEIN ALPHA SUBUNIT, GQ and the subsequently activates TYPE C PHOSPHOLIPASES. Additional evidence has shown that the receptor can act through a calcium-dependent signaling pathway.
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