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Shuh Narumiya - One of the best experts on this subject based on the ideXlab platform.
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the role of thromboxane Prostanoid Receptor signaling in gastric ulcer healing
International Journal of Experimental Pathology, 2021Co-Authors: Sakiko Yamane, Shuh Narumiya, Hideki Amano, Yoshiya Ito, Tomohiro Betto, Yoshio Matsui, Wasaburo Koizumi, Masataka MajimaAbstract:The process of gastric ulcer healing includes cell migration, proliferation, angiogenesis and re-epithelialization. Platelets contain angiogenesis stimulating factors that induce angiogenesis. Thromboxane A2 (TXA2 ) not only induces platelet activity but also angiogenesis. This study investigated the role of TXA2 in gastric ulcer healing using TXA2 Receptor knockout (TPKO) mice. Gastric ulcer healing was suppressed by treatment with the TXA2 synthase inhibitor OKY-046 and the TXA2 Receptor antagonist S-1452 compared with vehicle-treated mice. TPKO showed delayed gastric ulcer healing compared with wild-type mice (WT). The number of microvessels and CD31 expression were lower in TPKO than in WT mice, and TPKO suppressed the expression of transforming growth factor beta (TGF-β) and vascular endothelial growth factor A (VEGF-A) in areas around gastric ulcers. Immunofluorescence assays showed that TGF-β and VEGF-A co-localized with platelets. Gastric ulcer healing was significantly reduced in WT mice transplanted with TPKO compared with WT bone marrow. These results suggested that TP signalling on platelets facilitates gastric ulcer healing through TGF-β and VEGF-A.
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Prostanoid Receptors in gtopdb v 2021 2
IUPHAR BPS Guide to Pharmacology CITE, 2021Co-Authors: Lucie H Clapp, Shuh Narumiya, Yukihiko Sugimoto, Akos Heinemann, David F Woodward, Mark A Giembycz, Robert L Jones, Xavier Norel, Chengcan YaoAbstract:Prostanoid Receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Prostanoid Receptors [694]) are activated by the endogenous ligands prostaglandins PGD2, PGE1, PGE2 , PGF2α, PGH2, prostacyclin [PGI2] and thromboxane A2. Differences and similarities between human and rodent Prostanoid Receptor orthologues, and their specific roles in pathophysiologic conditions are reviewed in [448]. Measurement of the potency of PGI2 and thromboxane A2 is hampered by their instability in physiological salt solution; they are often replaced by cicaprost and U46619, respectively, in Receptor characterization studies.
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crystal structure of the endogenous agonist bound Prostanoid Receptor ep3
Nature Chemical Biology, 2019Co-Authors: Kazushi Morimoto, Shuh Narumiya, Ryoji Suno, Yunhong Hotta, Keitaro Yamashita, Kunio Hirata, Masaki Yamamoto, So Iwata, Takuya KobayashiAbstract:Prostanoids are a series of bioactive lipid metabolites that function in an autacoid manner via activation of cognate G-protein-coupled Receptors (GPCRs). Here, we report the crystal structure of human prostaglandin (PG) E Receptor subtype EP3 bound to endogenous ligand PGE2 at 2.90 A resolution. The structure reveals important insights into the activation mechanism of Prostanoid Receptors and provides a molecular basis for the binding modes of endogenous ligands. Structural analysis of prostaglandin E Receptor EP3, a member of the Prostanoid Receptor subfamily of GPCRs, in complex with the endogenous agonist PGE2 reveals important interactions and motions required for Receptor activation.
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exacerbation of aging associated and instability induced murine osteoarthritis with deletion of d Prostanoid Receptor 1 a prostaglandin d2 Receptor
Arthritis & Rheumatism, 2017Co-Authors: Yassine Ouhaddi, Shuh Narumiya, Sarahsalwa Nebbaki, L Habouri, Hassan Afif, Mohit Kapoor, Jeanpierre Pelletier, Johanne Martelpelletier, Bertrand Lussier, Mohamed BenderdourAbstract:Objective D Prostanoid Receptor 1 (DP1), a Receptor for prostaglandin D2 , plays important roles in inflammation and cartilage metabolism. However, its role in the pathogenesis of osteoarthritis (OA) remains unknown. This study was undertaken to explore the roles of DP1 in the development of OA in murine models and to evaluate the efficacy of a DP1 selective agonist in the treatment of OA. Methods The development of aging-associated OA and destabilization of the medial meniscus (DMM)-induced OA was compared between DP1-deficient (DP1-/- ) and wild-type (WT) mice. The progression of OA was assessed by histology, immunohistochemistry, and micro-computed tomography. Cartilage explants from DP1-/- and WT mice were treated with interleukin-1α (IL-1α) ex vivo, to evaluate proteoglycan degradation. The effect of intraperitoneal administration of the DP1 selective agonist BW245C on OA progression was evaluated in WT mice. Results Compared to WT mice, DP1-/- mice had exacerbated cartilage degradation in both models of OA, and this was associated with increased expression of matrix metalloproteinase 13 and ADAMTS-5. In addition, DP1-/- mice demonstrated enhanced subchondral bone changes. Cartilage explants from DP1-/- mice showed enhanced proteoglycan degradation following treatment with IL-1α. Intraperitoneal injection of BW245C attenuated the severity of DMM-induced cartilage degradation and bony changes in WT mice. Conclusion These findings indicate a critical role for DP1 signaling in OA pathogenesis. Modulation of the functions of DP1 may constitute a potential therapeutic target for the development of novel OA treatments.
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international union of basic and clinical pharmacology lxxxiii classification of Prostanoid Receptors updating 15 years of progress
Pharmacological Reviews, 2011Co-Authors: David F Woodward, R L Jones, Shuh NarumiyaAbstract:It is now more than 15 years since the molecular structures of the major Prostanoid Receptors were elucidated. Since then, substantial progress has been achieved with respect to distribution and function, signal transduction mechanisms, and the design of agonists and antagonists ( ). This review systematically details these advances. More recent developments in Prostanoid Receptor research are included. The DP2 Receptor, also termed CRTH2, has little structural resemblance to DP1 and other Receptors described in the original Prostanoid Receptor classification. DP2 Receptors are more closely related to chemoattractant Receptors. Prostanoid Receptors have also been found to heterodimerize with other Prostanoid Receptor subtypes and nonProstanoids. This may extend signal transduction pathways and create new ligand recognition sites: prostacyclin/thromboxane A2 heterodimeric Receptors for 8- epi -prostaglandin E2, wild-type/alternative (alt4) heterodimers for the prostaglandin FP Receptor for bimatoprost and the prostamides. It is anticipated that the 15 years of research progress described herein will lead to novel therapeutic entities.
Bradley K Wong - One of the best experts on this subject based on the ideXlab platform.
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bioactivation of a novel 2 methylindole containing dual chemoattractant Receptor homologous molecule expressed on t helper type 2 cells d Prostanoid Receptor antagonist leads to mechanism based cyp3a inactivation glutathione adduct characterization a
Drug Metabolism and Disposition, 2010Co-Authors: Simon Wong, Peter W Fan, Raju Subramanian, George Tonn, Kirk Henne, Michael G Johnson, Michelle Tadano Lohr, Bradley K WongAbstract:The 2-methyl substituted indole, 2MI [2-(4-(4-(2,4-dichlorophenylsulfonamido)-2-methyl-1 H -indol-5-yloxy)-3-methoxyphenyl)acetic acid] is a potent dual inhibitor of 1) chemoattractant Receptor-homologous molecule expressed on T-helper type-2 cells and 2) d-Prostanoid Receptor. During evaluation as a potential treatment for asthma and allergic rhinitis, 2MI was identified as a mechanism-based inactivator of CYP3A4 in vitro. The inactivation was shown to be irreversible by dialysis and accompanied by an NADPH-dependent increase in 2MI covalent binding to a 55- to 60-kDa microsomal protein, consistent with irreversible binding to CYP3A4. Two glutathione (GSH) adducts, G1 and G2, were identified in vitro, and the more abundant adduct (G1) was unambiguously determined via NMR to be GSH adducted to the 3-position of the 2-methylindole moiety. The potential for a clinical drug-drug interaction arising from mechanism-based inactivation of CYP3A4 by 2MI was predicted using a steady-state model, and a 4.3- to 7.5-fold increase in the exposure of midazolam was predicted at anticipated therapeutic concentrations. To better assess the potential for in vivo drug-drug interactions, the Sprague-Dawley rat was used as an in vivo model. An excellent in vitro-in vivo correlation was observed for the reduction in enzyme steady-state concentration ( E′ ss/ E ss) as well as the change in the exposure of a prototypical CYP3A substrate, indinavir (area under the curve (AUC) for indinavir/AUC). In summary, 2MI was identified as a potent mechanism-based inactivator of CYP3A and was predicted to elicit a clinically relevant drug-drug interaction in humans at an anticipated therapeutic concentration.
Antonio Garrido Montalban - One of the best experts on this subject based on the ideXlab platform.
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discovery of 2 1r 4r 4 4 chlorophenyl phenyl carbamoyl oxy methyl cyclohexyl methoxy acetate ralinepag an orally active prostacyclin Receptor agonist for the treatment of pulmonary arterial hypertension
Journal of Medicinal Chemistry, 2017Co-Authors: Thuyanh Tran, Bryan A Kramer, Youngjun Shin, Pureza Vallar, Douglas P Boatman, Carleton R Sage, Tawfik Gharbaoui, Ashwin M Krishnan, Sagar Shakya, Antonio Garrido MontalbanAbstract:The design and synthesis of a new series of potent non-Prostanoid IP Receptor agonists that showed oral efficacy in the rat monocrotaline model of pulmonary arterial hypertension (PAH) are described. Detailed profiling of a number of analogues resulted in the identification of 5c (ralinepag) that has good selectivity in both binding and functional assays with respect to most members of the Prostanoid Receptor family and a more modest 30- to 50-fold selectivity over the EP3 Receptor. In our hands, its potency and efficacy are comparable or superior to MRE269 (the active metabolite of the clinical compound NS-304) with respect to in vitro IP Receptor dependent cAMP accumulation assays. 5c had an excellent PK profile across species. Enterohepatic recirculation most probably contributes to a concentration–time profile after oral administration in the cynomolgus monkey that showed a very low peak-to-trough ratio. Following the identification of an acceptable solid form, 5c was selected for further development ...
Kathleen M Metters - One of the best experts on this subject based on the ideXlab platform.
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structure activity relationship of cinnamic acylsulfonamide analogues on the human ep3 Prostanoid Receptor
Bioorganic & Medicinal Chemistry, 2001Co-Authors: Helene Juteau, Nicole Sawyer, Marieclaude Carriere, Danielle Denis, Sonia Lamontagne, Nathalie Tremblay, Yves Gareau, Marc Labelle, Claudio Sturino, Kathleen M MettersAbstract:Potent and selective antagonists of the human EP3 Receptor have been identified. The structure-activity relationship of the chemical series was conducted and we found several analogues displaying sub-nanomolar K(i) values at the EP3 Receptor and micromolar activities at the EP1, EP2 and EP4 Receptors. The effect of added human serum albumin (HSA) on the binding affinity at the EP3 Receptor was also investigated.
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key structural features of prostaglandin e2 and Prostanoid analogs involved in binding and activation of the human ep1 Prostanoid Receptor
Molecular Pharmacology, 2001Co-Authors: Mark Ungrin, Rino Stocco, Nicole Sawyer, Kathleen M Metters, Marieclaude Carriere, Danielle Denis, Sonia Lamontagne, Nathalie Tremblay, Mark AbramovitzAbstract:The structure-activity relationship (SAR) of prostaglandin (PG) E(2) at the human EP(1) Prostanoid Receptor (designated hEP(1)) was examined via the binding and activation of this Receptor by a series of 55 Prostanoids and analogs. Using clonal human embryonic kidney 293 cell lines expressing recombinant hEP(1), affinity (K(i)), potency (EC(50)), and efficacy data were obtained using a radioligand competitive binding assay and an aequorin-based calcium functional assay. All compounds behaved as full agonists (90-100% of the response elicited by PGE(2)) in this assay, and the correlation between the K(i) and EC(50) values was highly significant (R(2) = 0.86). The results from the SAR analysis can be summarized as follows: 1) the existence and configuration of hydroxyl groups at the 11 and 15 positions of PGE(2) and Prostanoid analog structures play a critical role in agonist activity; 2) the carboxyl group is also important for activity and modification of the carboxylic acid to various esters results in greatly reduced affinity and potency; 3) the activity of structures with moderate or weak potency can be enhanced by modification of the omega-tail; and 4) modifications to the ketone at the 9-position are better tolerated, with 9-deoxy-9-methylene-PGE(2) being the most potent agonist tested in the functional assay. The impact of other modifications on agonist potency is also discussed. The results from this study have identified, for the first time, the key structural features of PGE(2) and related Prostanoids and Prostanoid analogs necessary for activation of hEP(1).
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new class of biphenylene dibenzazocinones as potent ligands for the human ep1 Prostanoid Receptor
Bioorganic & Medicinal Chemistry Letters, 1999Co-Authors: Rejean Ruel, Rino Stocco, Nicole Sawyer, Mark Abramovitz, Sonia Lamontagne, Nathalie Tremblay, Patrick Lacombe, Claude Godbout, C Rochette, Kathleen M MettersAbstract:A new class of potent and selective ligands for the human EP1 Prostanoid Receptor is described. SAR studies reported herein allowed the identification of several potent dibenzazocinones bearing an acylsulfonamide side chain. The binding affinity of these compounds on all eight human Prostanoid Receptors is reported.
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molecular cloning and characterization of the four rat prostaglandin e2 Prostanoid Receptor subtypes
European Journal of Pharmacology, 1997Co-Authors: Yves Boie, Rino Stocco, Nicole Sawyer, Deborah Slipetz, Mark Ungrin, Frank Neuschaferrube, Gerhard Puschel, Kathleen M Metters, Mark AbramovitzAbstract:Abstract We have characterized the rat Prostanoid EP1, EP2, EP3α and EP4 Receptor subtypes cloned from spleen, hepatocyte and/or kidney cDNA libraries. Comparison of the deduced amino acid sequences of the rat EP Receptors with their respective homologues from mouse and human showed 91% to 98% and 82% to 89% identity, respectively. RadioReceptor binding assays and functional assays were performed on EP Receptor expressing human embryonic kidney (HEK) 293 cells. The KD values obtained with prostaglandin E2 for the Prostanoid Receptor subtypes EP1, EP2, EP3α and EP4 were approximately 24, 5, 1 and 1 nM, respectively. The rank order of affinities for various Prostanoids at the Prostanoid Receptor subtypes EP2, EP3α and EP4 Receptor subtypes was prostaglandin E2=prostaglandin E1>iloprost>prostaglandin F2α>prostaglandin D2>U46619. The rank order at the Prostanoid EP1 Receptor was essentially the same except that iloprost had the highest affinity of the Prostanoids tested. Of the selective ligands, butaprost was selective for Prostanoid EP2, M&B28767 and sulprostone were selective for EP3α and enprostil displayed dual selectivity, interacting with both Prostanoid Receptor subtypes EP1 and EP3α. All four Receptors coupled to their predominant signal transduction pathways in HEK 293 cells. Notably, using a novel aequorin luminescence assay to monitor Prostanoid EP1 mediated increases in intracellular calcium, both iloprost and sulprostone were identified as partial agonists. Finally, by Northern blot analysis EP3 transcripts were most abundant in liver and kidney whereas Prostanoid EP2 Receptor mRNA was expressed in spleen, lung and testis and Prostanoid EP1 Receptor mRNA transcripts were predominantly expressed in the kidney. The rat Prostanoid EP1 probes also detected additional and abundant transcripts present in all the tissues examined. These were found to be related to the expression of a novel protein kinase gene and not the Prostanoid EP1 gene [Batshake, B., Sundelin, J., 1996. The mouse genes for the EP1 Prostanoid Receptor and the novel protein kinase overlap. Biochem. Biophys. Res. Commun. 227, 1329–1333].
Thuyanh Tran - One of the best experts on this subject based on the ideXlab platform.
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discovery of 2 1r 4r 4 4 chlorophenyl phenyl carbamoyl oxy methyl cyclohexyl methoxy acetate ralinepag an orally active prostacyclin Receptor agonist for the treatment of pulmonary arterial hypertension
Journal of Medicinal Chemistry, 2017Co-Authors: Thuyanh Tran, Bryan A Kramer, Youngjun Shin, Pureza Vallar, Douglas P Boatman, Carleton R Sage, Tawfik Gharbaoui, Ashwin M Krishnan, Sagar Shakya, Antonio Garrido MontalbanAbstract:The design and synthesis of a new series of potent non-Prostanoid IP Receptor agonists that showed oral efficacy in the rat monocrotaline model of pulmonary arterial hypertension (PAH) are described. Detailed profiling of a number of analogues resulted in the identification of 5c (ralinepag) that has good selectivity in both binding and functional assays with respect to most members of the Prostanoid Receptor family and a more modest 30- to 50-fold selectivity over the EP3 Receptor. In our hands, its potency and efficacy are comparable or superior to MRE269 (the active metabolite of the clinical compound NS-304) with respect to in vitro IP Receptor dependent cAMP accumulation assays. 5c had an excellent PK profile across species. Enterohepatic recirculation most probably contributes to a concentration–time profile after oral administration in the cynomolgus monkey that showed a very low peak-to-trough ratio. Following the identification of an acceptable solid form, 5c was selected for further development ...
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Discovery of 2‑(((1r,4r)‑4-(((4-Chlorophenyl)(phenyl)carbamoyl)oxy)methyl)cyclohexyl)methoxy)acetate (Ralinepag): An Orally Active Prostacyclin Receptor Agonist for the Treatment of Pulmonary Arterial Hypertension
2017Co-Authors: Thuyanh Tran, Youngjun Shin, Pureza Vallar, Douglas P Boatman, Carleton R Sage, Tawfik Gharbaoui, Bryan Kramer, Ning Zou, Ashwin Krishnan, Biman PalAbstract:The design and synthesis of a new series of potent non-Prostanoid IP Receptor agonists that showed oral efficacy in the rat monocrotaline model of pulmonary arterial hypertension (PAH) are described. Detailed profiling of a number of analogues resulted in the identification of 5c (ralinepag) that has good selectivity in both binding and functional assays with respect to most members of the Prostanoid Receptor family and a more modest 30- to 50-fold selectivity over the EP3 Receptor. In our hands, its potency and efficacy are comparable or superior to MRE269 (the active metabolite of the clinical compound NS-304) with respect to in vitro IP Receptor dependent cAMP accumulation assays. 5c had an excellent PK profile across species. Enterohepatic recirculation most probably contributes to a concentration–time profile after oral administration in the cynomolgus monkey that showed a very low peak-to-trough ratio. Following the identification of an acceptable solid form, 5c was selected for further development for the treatment of PAH
