ArticleThe Journal of biological chemistry2010
A novel biased allosteric compound inhibitor of parturition selectively impedes the prostaglandin F2alpha-mediated Rho/ROCK signaling pathway.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 97 citations in OpenAlex.
- Structural Perspectives on Biased Allostery of GPCR Signaling.Handbook of experimental pharmacology · 2026Review
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- A novel modulator of IL-6R prevents inflammation-induced preterm birth and improves newborn outcome.EMBO molecular medicine · 2025Article
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- Structural and dynamic insights into supra-physiological activation and allosteric modulation of a muscarinic acetylcholine receptor.Nature communications · 2023Article
- PGFEMBO molecular medicine · 2023Article
- PGFFrontiers in pharmacology · 2023Article
- Prostaglandin F2α requires activation of calcium-dependent signalling to trigger inflammation in human myometrium.Frontiers in endocrinology · 2023Article
- Brimonidine Modulates the ROCK1 Signaling Effects on Adipogenic Differentiation in 2D and 3D 3T3-L1 Cells.Bioengineering (Basel, Switzerland) · 2022Article
- Article
- GαFrontiers in cell and developmental biology · 2022Review
- Biased Allosteric Modulators: New Frontiers in GPCR Drug Discovery.Trends in pharmacological sciences · 2021Review
- G protein-coupled receptors: structure- and function-based drug discovery.Signal transduction and targeted therapy · 2021Review
- Allosteric Modulator Leads Hiding in Plain Site: Developing Peptide and Peptidomimetics as GPCR Allosteric Modulators.Frontiers in chemistry · 2021Review
- The PAR2 inhibitor I-287 selectively targets GαCommunications biology · 2020Article
- New Advances in Targeting the Resolution of Inflammation: Implications for Specialized Pro-Resolving Mediator GPCR Drug Discovery.ACS pharmacology & translational science · 2020Review
- Interleukin-1 Receptor Modulation Using β-Substituted α-Amino-γ-Lactam Peptides From Solid-Phase Synthesis and Diversification.Frontiers in chemistry · 2020Article
- Fine Tuning Muscarinic Acetylcholine Receptor Signaling Through Allostery and Bias.Frontiers in pharmacology · 2020Review
- Application ofMolecules (Basel, Switzerland) · 2019Article
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Authors and funding
16 authors at 4 institutions in 2 countries.
Funding
Abstract
The prostaglandin F2alpha (PGF2alpha) receptor (FP) is a key regulator of parturition and a target for pharmacological management of preterm labor. However, an incomplete understanding of signaling pathways regulating myometrial contraction hinders the development of improved therapeutics. Here we used a peptidomimetic inhibitor of parturition in mice, PDC113.824, whose structure was based on the NH(2)-terminal region of the second extracellular loop of FP receptor, to gain mechanistic insight underlying FP receptor-mediated cell responses in the context of parturition. We show that PDC113.824 not only delayed normal parturition in mice but also that it inhibited both PGF2alpha- and lipopolysaccharide-induced preterm labor. PDC113.824 inhibited PGF2alpha-mediated, G(alpha)(12)-dependent activation of the Rho/ROCK signaling pathways, actin remodeling, and contraction of human myometrial cells likely by acting as a non-competitive, allosteric modulator of PGF2alpha binding. In contrast to its negative allosteric modulating effects on Rho/ROCK signaling, PDC113.824 acted as a positive allosteric modulator on PGF2alpha-mediated protein kinase C and ERK1/2 signaling. This bias in receptor-dependent signaling was explained by an increase in FP receptor coupling to G(alpha)(q), at the expense of coupling to G(alpha)(12). Our findings regarding the allosteric and biased nature of PDC113.824 offer new mechanistic insights into FP receptor signaling relevant to parturition and suggest novel therapeutic opportunities for the development of new tocolytic drugs.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.