Rivenprost
(Synonyms: ONO-4819) 目录号 : GC44845
An EP4 receptor agonist
Cas No.:256382-08-8
Sample solution is provided at 25 µL, 10mM.
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Prostaglandin E2 activates four distinct G protein-coupled receptors, EP1-4. Rivenprost is a potent and selective agonist for the EP4 receptor (Ki = 0.7, 56, 620, and >10,000 nM for EP4, EP3, EP2, and EP1, respectively). It has been used to promote EP4-mediated bone formation, prevent bone loss related to osteoporosis, drive osteoblast differentiation, and stabilize bone implants.[1][2][3][4][5] Rivenprost has also been used to support wound healing.[6]
Reference:
[1]. Yoshida, K., Oida, H., Kobayashi, T., et al. Stimulation of bone formation and prevention of bone loss by prostaglandin E EP4 receptor activation. Proceedings of the National Academy of Sciences of the United States of America 99(7), 4580-4585 (2002).
[2]. Ninomiya, T., Hosoya, A., Hiraga, T., et al. Prostaglandin E2 receptor EP4-selective agonist (ONO-4819) increases bone formation by modulating mesenchymal cell differentiation. European Journal of Pharmacology 650, 396-402 (2011).
[3]. Ito, M., Nakayama, K., Konaka, A., et al. Effects of a prostaglandin EP4 agonist, ONO-4819, and risedronate on trabecular microstructure and bone strength in mature ovariectomized rats. Bone 39, 453-459 (2006).
[4]. Nakagawa, K., Imai, Y., Ohta, Y., et al. Prostaglandin E2 EP4 agonist (ONO-4819) accelerates BMP-induced osteoblastic differentiation. Bone 41, 543-548 (2007).
[5]. Hayashi, K., Fotovati, A., Abu Ali, S., et al. Effect of a prostaglandin EP4 receptor agonist on early fixation of hydroxyapatite/titanium composite- and titanium-coated rough-surfaced implants in ovariectomized rats. J.Biomed.Mater.Res.A 92(3), 1202-1209 (2010).
[6]. Honma, Y., Arai, I., Hashimoto, Y., et al. Prostaglandin D2 and prostaglandin E2 accelerate the recovery of cutaneous barrier disruption induced by mechanical scratching in mice. European Journal of Pharmacology 518, 56-62 (2005).
Improved homology modeling of the human & rat EP4 prostanoid receptors
BMC Mol Cell Biol 2019 Aug 27;20(1):37.PMID:31455205DOI:10.1186/s12860-019-0212-5.
Background: The EP4 prostanoid receptor is one of four GPCRs that mediate the diverse actions of prostaglandin E2 (PGE2). Novel selective EP4 receptor agonists would assist to further elucidate receptor sub-type function and promote development of therapeutics for bone healing, heart failure, and other receptor associated conditions. The rat EP4 (rEP4) receptor has been used as a surrogate for the human EP4 (hEP4) receptor in multiple SAR studies. To better understand the validity of this traditional approach, homology models were generated by threading for both receptors using the RaptorX server. These models were fit to an implicit membrane using the PPM server and OPM database with refinement of intra and extracellular loops by Prime (Schrödinger). To understand the interaction between the receptors and known agonists, induced-fit docking experiments were performed using Glide and Prime (Schrödinger), with both endogenous agonists and receptor sub-type selective, small-molecule agonists. The docking scores and observed interactions were compared with radioligand displacement experiments and receptor (rat & human) activation assays monitoring cAMP. Results: Rank-ordering of in silico compound docking scores aligned well with in vitro activity assay EC50 and radioligand binding Ki. We observed variations between rat and human EP4 binding pockets that have implications in future small-molecule receptor-modulator design and SAR, specifically a S103G mutation within the rEP4 receptor. Additionally, these models helped identify key interactions between the EP4 receptor and ligands including PGE2 and several known sub-type selective agonists while serving as a marked improvement over the previously reported models. Conclusions: This work has generated a set of novel homology models of the rEP4 and hEP4 receptors. The homology models provide an improvement upon the previously reported model, largely due to improved solvation. The hEP4 docking scores correlates best with the cAMP activation data, where both data sets rank order Rivenprost>CAY10684 > PGE1 ≈ PGE2 > 11-deoxy-PGE1 ≈ 11-dexoy-PGE2 > 8-aza-11-deoxy-PGE1. This rank-ordering matches closely with the rEP4 receptor as well. Species-specific differences were noted for the weak agonists Sulprostone and Misoprostol, which appear to dock more readily within human receptor versus rat receptor.
Prostaglandin E2-Transporting Pathway and Its Roles via EP2/EP4 in Cultured Human Dental Pulp
J Endod 2023 Apr;49(4):410-418.PMID:36758673DOI:10.1016/j.joen.2023.01.009.
Introduction: Prostaglandin E2 (PGE2) exerts biological actions through its transport pathway involving intracellular synthesis, extracellular transport, and receptor binding. This study aimed to determine the localization of the components of the PGE2-transporting pathway in human dental pulp and explore the relevance of PGE2 receptors (EP2/EP4) to angiogenesis and dentinogenesis. Methods: Protein localization of microsomal PGE2 (mPGES)synthase, PGE2 transporters (multidrug resistance-associated protein-4 [MRP4] and prostaglandin transporter [PGT]), and EP2/EP4 was analyzed using double immunofluorescence staining. Tooth slices from human third molars were cultured with or without butaprost (EP2 agonist) or Rivenprost (EP4 agonist) for 1 week. Morphometric analysis of endothelial cell filopodia was performed to evaluate angiogenesis, and real-time polymerase chain reaction was performed to evaluate angiogenesis and odontoblast differentiation markers. Results: MRP4 and PGT were colocalized with mPGES and EP2/EP4 in odontoblasts and endothelial cells. Furthermore, MRP4 was colocalized with mPGES and EP4 in human leukocyte antigen-DR-expressing dendritic cells. In the tooth slice culture, EP2/EP4 agonists induced significant increases in the number and length of filopodia and mRNA expression of angiogenesis markers (vascular endothelial growth factor and fibroblast growth factor-2) and odontoblast differentiation markers (dentin sialophosphoprotein and collagen type 1). Conclusions: PGE2-producing enzyme (mPGES), transporters (MRP4 and PGT), and PGE2-specific receptors (EP2/EP4) were immunolocalized in various cellular components of the human dental pulp. EP2/EP4 agonists promoted endothelial cell filopodia generation and upregulated angiogenesis- and odontoblast differentiation-related genes, suggesting that PGE2 binding to EP2/EP4 is associated with angiogenic and dentinogenic responses.
The EP3 and EP4 Receptor Subtypes both Mediate the Fever-producing Effects of Prostaglandin E2 in the Rostral Ventromedial Preoptic Area of the Hypothalamus in Rats
Neuroscience 2022 Jul 1;494:25-37.PMID:35550162DOI:10.1016/j.neuroscience.2022.05.001.
This study aimed to re-examine the receptor subtype that mediates the fever-producing effects of prostaglandin E2 (PGE2) in the rostral ventromedial preoptic area (rvmPOA) of the hypothalamus. Among the four subtypes of PGE2 receptors (EP1, EP2, EP3, and EP4), EP3 receptor is crucially involved in the febrile effects of PGE2. However, it is possible for other subtypes of PGE2 receptor to contribute in the central mechanism of fever generation. Accordingly, effects of microinjection of PGE2 receptor subtype-specific agonists or antagonists were examined at the locus where a microinjection of a small amount (420 fmol) of PGE2 elicited prompt increases in the O2 consumption rate (VO2), heart rate, and colonic temperature (Tc) in the rvmPOA of urethane-chloralose-anesthetized rats. The EP3 agonist sulprostone mimicked, whereas its antagonist L-798,106 reduced, the febrile effects of PGE2 microinjected into the same site. Similarly, the EP4 agonist Rivenprost mimicked, whereas its antagonist ONO-AE3-208 reduced, the effects of PGE2 microinjected into the same site. In contrast, microinjection of the EP1 agonist iloprost induced a very small increase in VO2 but did not have significant influences on the heart rate and Tc, whereas its antagonist, AH6809, did not affect the PGE2-induced responses. Microinjection of the EP2 agonist butaprost had no effects on the VO2, heart rate, and Tc. The results suggest that the EP3 and EP4 receptor subtypes are both involved in the fever generated by PGE2 in the rvmPOA.