title: Targeting the prostaglandin F2α receptor for preventing preterm labor with azapeptide tocolytics.
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.
authors.affiliation: Department of Medicine, McGill University Health Center Research Institute, Montréal H3A 1A1, Québec, Canada.
authors.forename: Carine B
authors.initials: CB
authors.lastname: Bourguet
authors.forename: Eugénie
authors.initials: E
authors.lastname: Goupil
authors.forename: Danaë
authors.initials: D
authors.lastname: Tassy
authors.forename: Xin
authors.initials: X
authors.lastname: Hou
authors.forename: Eryk
authors.initials: E
authors.lastname: Thouin
authors.forename: Felix
authors.initials: F
authors.lastname: Polyak
authors.forename: Terence E
authors.initials: TE
authors.lastname: Hébert
authors.forename: Audrey
authors.initials: A
authors.lastname: Claing
authors.forename: Stéphane A
authors.initials: SA
authors.lastname: Laporte
authors.forename: Sylvain
authors.initials: S
authors.lastname: Chemtob
authors.forename: William D
authors.initials: WD
authors.lastname: Lubell
mesh_terms: D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D002478:Cells, Cultured; D015237:Dinoprost / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D007752:Obstetric Labor, Premature / Q000517:prevention & control*; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000187:drug effects; D011982:Receptors, Prostaglandin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D015149:Tocolytic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014590:Uterine Contraction / Q000187:drug effects*; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D001372:Aza Compounds; D010446:Peptide Fragments; D011982:Receptors, Prostaglandin; D015149:Tocolytic Agents; C034671:prostaglandin F2alpha receptor; D015237:Dinoprost; D054460:rho-Associated Kinases; D048049:Extracellular Signal-Regulated MAP Kinases