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Evi Kostenis - One of the best experts on this subject based on the ideXlab platform.
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synthesis and in vitro evaluation of a selective antagonist and the corresponding radioligand for the Prostaglandin D2 Receptor crth2
Bioorganic & Medicinal Chemistry Letters, 2007Co-Authors: Trond Ulven, Michael J Gallen, Mads Corvinius Nielsen, Nicole Merten, Carola Schmidt, Klaus Mohr, Christian Trankle, Evi KostenisAbstract:Abstract Synthesis and preliminary in vitro biological evaluation of a selective high-affinity CRTH2 antagonist is described. The stability of an N-benzyl group facilitated synthesis of the corresponding radioligand by tritiation of a brominated precursor. The compound [3H]TRQ11238 represents the first selective CRTH2 antagonist radioligand and exhibited a specific radioactivity of 52 Ci/mmol and a pKd of 9.0.
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the role of the Prostaglandin D2 Receptor dp in eosinophil trafficking
Journal of Immunology, 2007Co-Authors: Petra Schratl, Trond Ulven, Evi Kostenis, Julia F Royer, Eva M Sturm, Maria Waldhoer, Gerald Hoefler, Rufina Schuligoi, Irmgard Th Lippe, B A PeskarAbstract:Prostaglandin (PG) D2 is a major mast cell product that acts via two Receptors, the D-type prostanoid (DP) and the chemoattractant Receptor-homologous molecule expressed on Th2 cells (CRTH2) Receptors. Whereas CRTH2 mediates the chemotaxis of eosinophils, basophils, and Th2 lymphocytes, the role of DP has remained unclear. We report in this study that, in addition to CRTH2, the DP Receptor plays an important role in eosinophil trafficking. First, we investigated the release of eosinophils from bone marrow using the in situ perfused guinea pig hind limb preparation. PGD2 induced the rapid release of eosinophils from bone marrow and this effect was inhibited by either the DP Receptor antagonist BWA868c or the CRTH2 Receptor antagonist ramatroban. In contrast, BWA868c did not inhibit the release of bone marrow eosinophils when this was induced by the CRTH2-selective agonist 13,14-dihydro-15-keto-PGD2. In additional experiments, we isolated bone marrow eosinophils from the femoral cavity and found that these cells migrated toward PGD2. We also observed that BWA868c inhibited this response to a similar extent as ramatroban. Finally, using immunohistochemistry we could demonstrate that eosinophils in human bone marrow specimens expressed DP and CRTH2 Receptors at similar levels. Eosinophils isolated from human peripheral blood likewise expressed DP Receptor protein but at lower levels than CRTH2. In agreement with this, the chemotaxis of human peripheral blood eosinophils was inhibited both by BWA868c and ramatroban. These findings suggest that DP Receptors comediate with CRTH2 the mobilization of eosinophils from bone marrow and their chemotaxis, which might provide the rationale for DP antagonists in the treatment of allergic disease.
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antagonism of the Prostaglandin D2 Receptor crth2 attenuates asthma pathology in mouse eosinophilic airway inflammation
Respiratory Research, 2007Co-Authors: Lena Uller, Lisa Alenmyr, Magnus Korsgren, Trond Ulven, Thomas Hogberg, Gunnar Andersson, Carl G A Persson, Jesper Mosolff Mathiesen, Evi KostenisAbstract:Background Mast cell-derived Prostaglandin D2 (PGD2), may contribute to eosinophilic inflammation and mucus production in allergic asthma. Chemoattractant Receptor homologous molecule expressed on TH2 cells (CRTH2), a high affinity Receptor for Prostaglandin D2, mediates trafficking of TH2-cells, mast cells, and eosinophils to inflammatory sites, and has recently attracted interest as target for treatment of allergic airway diseases. The present study involving mice explores the specificity of CRTH2 antagonism of TM30089, which is structurally closely related to the dual TP/CRTH2 antagonist ramatroban, and compares the ability of ramatroban and TM30089 to inhibit asthma-like pathology.
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on the mechanism of interaction of potent surmountable and insurmountable antagonists with the Prostaglandin D2 Receptor crth2
Molecular Pharmacology, 2006Co-Authors: Jesper Mosolff Mathiesen, Trond Ulven, Julia F Royer, Arthur Christopoulos, Mercedes Campillo, Akos Heinemann, Leonardo Pardo, Evi KostenisAbstract:Chemoattractant Receptor-homologous molecule expressed on T helper 2 cells (CRTH2) has attracted interest as a potential therapeutic target in inflammatory diseases. Ramatroban, a thromboxane A2 Receptor antagonist with clinical efficacy in allergic rhinitis, was recently found to also display potent CRTH2 antagonistic activity. Here, we present the pharmacological profile of three ramatroban analogs that differ chemically from ramatroban by either a single additional methyl group (TM30642), or an acetic acid instead of a propionic acid side chain (TM30643), or both modifications (TM30089). All three compounds bound to human CRTH2 stably expressed in human embryonic kidney 293 cells with nanomolar affinity. [3H]Prostaglandin D2 (PGD2) saturation analysis reveals that ramatroban and TM30642 decrease PGD2 affinity, whereas TM30643 and TM30089 exclusively depress ligand binding capacity ( B max). Each of the three compounds acted as potent CRTH2 antagonists, yet the nature of their antagonism differed markedly. In functional assays measuring inhibition of PGD2-mediated 1) guanosine 5′- O -(3-thio)triphosphate binding, 2) β-arrestin translocation, and 3) shape change of human eosinophils endogenously expressing CRTH2, ramatroban, and TM30642 produced surmountable antagonism and parallel rightward shifts of the PGD2 concentration-response curves. For TM30643 and TM30089, this shift was accompanied by a progressive reduction of maximal response. Binding analyses indicated that the functional insurmountability of TM30643 and TM30089 was probably related to long-lasting CRTH2 inhibition mediated via the orthosteric site of the Receptor. A mechanistic understanding of insurmountability of CRTH2 antagonists could be fundamental for development of this novel class of anti-inflammatory drugs.
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On the mechanism of interaction of potent surmountable and insurmountable antagonists with the Prostaglandin D2 Receptor CRTH2.
Molecular pharmacology, 2006Co-Authors: Jesper Mosolff Mathiesen, Trond Ulven, Julia F Royer, Arthur Christopoulos, Mercedes Campillo, Akos Heinemann, Leonardo Pardo, Evi KostenisAbstract:Chemoattractant Receptor-homologous molecule expressed on T helper 2 cells (CRTH2) has attracted interest as a potential therapeutic target in inflammatory diseases. Ramatroban, a thromboxane A2 Receptor antagonist with clinical efficacy in allergic rhinitis, was recently found to also display potent CRTH2 antagonistic activity. Here, we present the pharmacological profile of three ramatroban analogs that differ chemically from ramatroban by either a single additional methyl group (TM30642), or an acetic acid instead of a propionic acid side chain (TM30643), or both modifications (TM30089). All three compounds bound to human CRTH2 stably expressed in human embryonic kidney 293 cells with nanomolar affinity. [3H]Prostaglandin D2 (PGD2) saturation analysis reveals that ramatroban and TM30642 decrease PGD2 affinity, whereas TM30643 and TM30089 exclusively depress ligand binding capacity (Bmax). Each of the three compounds acted as potent CRTH2 antagonists, yet the nature of their antagonism differed markedly. In functional assays measuring inhibition of PGD2-mediated 1) guanosine 5'-O-(3-thio)triphosphate binding, 2) beta-arrestin translocation, and 3) shape change of human eosinophils endogenously expressing CRTH2, ramatroban, and TM30642 produced surmountable antagonism and parallel rightward shifts of the PGD2 concentration-response curves. For TM30643 and TM30089, this shift was accompanied by a progressive reduction of maximal response. Binding analyses indicated that the functional insurmountability of TM30643 and TM30089 was probably related to long-lasting CRTH2 inhibition mediated via the orthosteric site of the Receptor. A mechanistic understanding of insurmountability of CRTH2 antagonists could be fundamental for development of this novel class of anti-inflammatory drugs.
Eseng Lai - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetics of Laropiprant, a Selective Prostaglandin D2 Receptor 1 Antagonist, in Patients With Moderate Hepatic Impairment
The Journal of Clinical Pharmacology, 2011Co-Authors: Ying-hong Wang, John A Wagner, Fang Liu, Amy O. Johnson-levonas, Kenneth C. Lasseter, Julie Ann Mabalot Luk, Ajay Nirula, Thomas Marbury, N. Martin Lunde, Eseng LaiAbstract:This open-label study evaluated the influence of hepatic insufficiency on the pharmacokinetics of laropiprant (LRPT), a Prostaglandin D 2 Receptor-1 antagonist, to guide clinicians in the event of inadvertent dosing in patients with hepatic insufficiency. A single oral 4 0-mg dose of LRPT was administered to 8 patients with moderate hepatic insufficiency and 8 healthy control participants matched for important baseline characteristics. Blood samples were collected predose and up to 96 hours post-dose to assess LRPT pharmacokinetics. No clinically significant effect of hepatic insufficiency would be declared if the 90% confidence interval (CI) for the estimated geometric mean ratio (GMR; hepatic insufficiency patients/ healthy participants) of AUC 0-∞ was contained within the prespecified bounds of (0.50-3.00). Estimated GMRs of AUC 0-∞ and C max (90% CIs) were 2.78 (1.71, 4.50) and 2.17 (1.33, 3.53), respectively. The median time to C max and apparent terminal t 1/2 of LRPT were comparable between the 2 populations (P > .100). Single-dose LPRT 40 mg was generally well tolerated in all patients. The plasma pharmacokinetics of a single 40-mg oral dose of LRPT is not similar between patients with moderate hepatic insufficiency and matched healthy participants. The GMR (90% CI) of AUC 0-∞ for patients with moderate hepatic insufficiency versus matched controls was 2.78 (1.71, 4.50).
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Effects of Laropiprant, a Selective Prostaglandin D2 Receptor 1 Antagonist, on the Steady‐State Pharmacokinetics of Digoxin in Healthy Adult Subjects
Journal of clinical pharmacology, 2010Co-Authors: Fang Liu, John A Wagner, Amy O. Johnson-levonas, Laura K. Vessey, Larissa A. Wenning, Sandra M. Connolly, Melissa Buckland, Andrew Denker, Eseng LaiAbstract:Laropiprant, a Prostaglandin D(2) Receptor-1 antagonist shown to reduce flushing symptoms, has been combined with niacin for treatment of dyslipidemia. This open-label, randomized, 2-period crossover study assessed the effects of laropiprant on the pharmacokinetics of digoxin, with 13 healthy subjects randomized to 2 treatments administered in random order with a 10-day or longer washout period: (A) single-dose digoxin 0.5 mg on day 1 and once-daily oral doses of laropiprant 40 mg for 10 days beginning 5 days prior to digoxin dosing (day -5 to day 5); (B) single-dose digoxin 0.5 mg on day 1. Blood was collected over the course of 120 hours post digoxin dose to assess pharmacokinetics of immunoreactive digoxin. Comparability was declared if the 90% confidence interval for the geometric mean ratio of laropiprant+digoxin to digoxin alone of the area under the plasma concentration-time curve from time 0 to infinity (AUC(0-infinity)) for immunoreactive digoxin fell within 0.80 to 1.25. The AUC(0-infinity) and maximum observed plasma concentration (C(max)) geometric mean ratios of immunoreactive digoxin were 0.91 (90% confidence interval, 0.76-1.10) and 1.04 (90% confidence interval, 0.91-1.21), respectively. Median time of occurrence of C(max) and mean half-life of immunoreactive digoxin were comparable in the presence and absence of laropiprant. Coadministration of digoxin and laropiprant was generally well tolerated. The small decrease in exposure to immunoreactive digoxin (approximately 10%) following coadministration of laropiprant and digoxin is not considered to be clinically meaningful.
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effects of aspirin when added to the Prostaglandin D2 Receptor antagonist laropiprant on niacin induced flushing symptoms
The Journal of Clinical Pharmacology, 2009Co-Authors: Victor Dishy, John A Wagner, Fang Liu, David L Ebel, George Atiee, Jane Royalty, Sandra Reilley, John F Paolini, Eseng LaiAbstract:Niacin is an effective lipid-modifying therapy whose use has been limited by suboptimal tolerability. The adverse effect of flushing is due to Prostaglandin D 2 (PGD 2 )-mediated cutaneous vasodilation. Adjunctive treatment with the PGD 2 Receptor antagonist laropiprant significantly reduces the incidence and severity of niacin-induced flushing. The objective of this study was to assess the effect of aspirin pretreatment on flushing symptoms with extended-release (ER) niacin/laropiprant in healthy volunteers. A randomized, double-blind, placebo-controlled crossover study compared patient-rated flushing following pretreatment with aspirin 325 mg versus placebo administered 30 minutes before ER niacin 2 g/laropiprant 40 mg. Flushing responses were assessed using participant-reported overall symptom severity score (OSSS), including individual characteristics of redness, warmth, tingling, or itching. The overall incidence and severity of flushing were comparable for participants receiving aspirin or placebo before ER niacin 2 g/laropiprant 40 mg. The difference in 3-day average OSSS between treatments was 0.2 (P= .180). Profiles of flushing severity, frequency, and bothersomeness were comparable for the aspirin/ER niacin/ laropiprant and ER niacin/laropiprant regimens. All treatments were safe and well tolerated. Coadministration of aspirin 325 mg daily with ER niacin 2 g/laropiprant 40 mg does not further reduce residual flushing symptoms associated with ER niacin 2 g/laropiprant 40 mg alone.
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Effects of Aspirin When Added to the Prostaglandin D2 Receptor Antagonist Laropiprant on Niacin‐Induced Flushing Symptoms
Journal of clinical pharmacology, 2009Co-Authors: Victor Dishy, John A Wagner, Fang Liu, David L Ebel, George Atiee, Jane Royalty, Sandra Reilley, John F Paolini, Eseng LaiAbstract:Niacin is an effective lipid-modifying therapy whose use has been limited by suboptimal tolerability. The adverse effect of flushing is due to Prostaglandin D 2 (PGD 2 )-mediated cutaneous vasodilation. Adjunctive treatment with the PGD 2 Receptor antagonist laropiprant significantly reduces the incidence and severity of niacin-induced flushing. The objective of this study was to assess the effect of aspirin pretreatment on flushing symptoms with extended-release (ER) niacin/laropiprant in healthy volunteers. A randomized, double-blind, placebo-controlled crossover study compared patient-rated flushing following pretreatment with aspirin 325 mg versus placebo administered 30 minutes before ER niacin 2 g/laropiprant 40 mg. Flushing responses were assessed using participant-reported overall symptom severity score (OSSS), including individual characteristics of redness, warmth, tingling, or itching. The overall incidence and severity of flushing were comparable for participants receiving aspirin or placebo before ER niacin 2 g/laropiprant 40 mg. The difference in 3-day average OSSS between treatments was 0.2 (P= .180). Profiles of flushing severity, frequency, and bothersomeness were comparable for the aspirin/ER niacin/ laropiprant and ER niacin/laropiprant regimens. All treatments were safe and well tolerated. Coadministration of aspirin 325 mg daily with ER niacin 2 g/laropiprant 40 mg does not further reduce residual flushing symptoms associated with ER niacin 2 g/laropiprant 40 mg alone.
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Effects of Laropiprant, a Selective Prostaglandin D2 Receptor 1 Antagonist, on the Pharmacokinetics of Rosiglitazone
Cardiovascular therapeutics, 2009Co-Authors: Jules I. Schwartz, Mark Stroh, Bing Gao, Fang Liu, Kimberly Rosko, Stefan Zajic, Alan J. Meehan, Jon L. Ruckle, Eseng Lai, John A WagnerAbstract:Laropiprant (LRPT), a Prostaglandin D2 Receptor-1 antagonist shown to reduce niacin-induced flushing symptoms, has been combined with niacin for treatment of dyslipidemia. This open-label, randomized, 2-period crossover study assessed the pharmacokinetics of single-dose rosiglitazone in the presence and absence of multiple-dose LRPT. Twelve healthy male and female subjects, 34–64 years of age, received two, once-daily oral treatments in random sequence separated by ≥3-day washout: (1) multiple-dose LRPT 40 mg/day for 7 days (Days 1 to 7) coadministered with single-dose rosiglitazone 4 mg on Day 6; (2) single-dose rosiglitazone 4 mg on Day 1. Comparability was declared because the 90% confidence interval (CI) for the AUC0-∞ geometric mean ratio (GMR; rosiglitazone + LRPT/rosiglitazone alone) [0.92 (0.86, 0.99)], was contained within prespecified bounds (0.70, 1.43). The Cmax GMR (90% CI) for rosiglitazone was 0.98 (0.95, 1.02). There was no evidence of clinically meaningful alterations in the pharmacokinetics of rosiglitazone, a probe CYP2C8 substrate, following coadministration of multiple-dose LRPT in healthy subjects. Therefore, findings suggest that LRPT does not inhibit CYP2C8-mediated metabolism.
Dan Lindholm - One of the best experts on this subject based on the ideXlab platform.
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Prostaglandin D2 Receptor DP1 Antibodies Predict Vaccine-induced and Spontaneous Narcolepsy Type 1: Large-scale Study of Antibody Profiling
EBioMedicine, 2018Co-Authors: Helle Sadam, Anri Kivil, Mariliis Jaago, Priit Adler, Susan Pihelgas, Olli Vapalahti, Toomas Neuman, Arno Pihlak, Jaak Vilo, Dan LindholmAbstract:Background: Neuropathological findings support an autoimmune etiology as an underlying factor for loss of orexin-producing neurons in spontaneous narcolepsy type 1 (narcolepsy with cataplexy; sNT1) as well as in Pandemrix influenza vaccine-induced narcolepsy type 1 (Pdmx-NT1). The precise molecular target or antigens for the immune response have, however, remained elusive. Methods: Here we have performed a comprehensive antigenic repertoire analysis of sera using the next-generation phage display method - mimotope variation analysis (MVA). Samples from 64 children and adolescents were analyzed: 10 with Pdmx-NT1, 6 with sNT1, 16 Pandemrix-vaccinated, 16 H1N1 infected, and 16 unvaccinated healthy individuals. The diagnosis of NT1 was defined by the American Academy of Sleep Medicine international criteria of sleep disorders v3. Findings: Our data showed that although the immunoprofiles toward vaccination were generally similar in study groups, there were also striking differences in immunoprofiles between sNT1 and Pdmx-NT1 groups as compared with controls. Prominent immune response was observed to a peptide epitope derived from Prostaglandin D2 Receptor (DP1), as well as peptides homologous to B cell lymphoma 6 protein. Further validation confirmed that these can act as true antigenic targets in discriminating NT1 diseased along with a novel epitope of hemagglutinin of H1N1 to delineate exposure to H1N1. Interpretation: We propose that DP1 is a novel molecular target of autoimmune response and presents a potential diagnostic biomarker for NT1. DP1 is involved in the regulation of non-rapid eye movement (NREM) sleep and thus alterations in its functions could contribute to the disturbed sleep regulation in NT1 that warrants further studies. Together our results also show that MVA is a helpful method for finding novel peptide antigens to classify human autoimmune diseases, possibly facilitating the design of better therapies.
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Prostaglandin D2 Receptor DP1 Antibodies Predict Vaccine-induced and Spontaneous Narcolepsy Type 1: Large-scale Study of Antibody Profiling
Elsevier, 2018Co-Authors: Helle Sadam, Anri Kivil, Mariliis Jaago, Priit Adler, Susan Pihelgas, Olli Vapalahti, Toomas Neuman, Arno Pihlak, Jaak Vilo, Dan LindholmAbstract:Background: Neuropathological findings support an autoimmune etiology as an underlying factor for loss of orexin-producing neurons in spontaneous narcolepsy type 1 (narcolepsy with cataplexy; sNT1) as well as in Pandemrix influenza vaccine-induced narcolepsy type 1 (Pdmx-NT1). The precise molecular target or antigens for the immune response have, however, remained elusive. Methods: Here we have performed a comprehensive antigenic repertoire analysis of sera using the next-generation phage display method - mimotope variation analysis (MVA). Samples from 64 children and adolescents were analyzed: 10 with Pdmx-NT1, 6 with sNT1, 16 Pandemrix-vaccinated, 16 H1N1 infected, and 16 unvaccinated healthy individuals. The diagnosis of NT1 was defined by the American Academy of Sleep Medicine international criteria of sleep disorders v3. Findings: Our data showed that although the immunoprofiles toward vaccination were generally similar in study groups, there were also striking differences in immunoprofiles between sNT1 and Pdmx-NT1 groups as compared with controls. Prominent immune response was observed to a peptide epitope derived from Prostaglandin D2 Receptor (DP1), as well as peptides homologous to B cell lymphoma 6 protein. Further validation confirmed that these can act as true antigenic targets in discriminating NT1 diseased along with a novel epitope of hemagglutinin of H1N1 to delineate exposure to H1N1. Interpretation: We propose that DP1 is a novel molecular target of autoimmune response and presents a potential diagnostic biomarker for NT1. DP1 is involved in the regulation of non-rapid eye movement (NREM) sleep and thus alterations in its functions could contribute to the disturbed sleep regulation in NT1 that warrants further studies. Together our results also show that MVA is a helpful method for finding novel peptide antigens to classify human autoimmune diseases, possibly facilitating the design of better therapies. Keywords: Narcolepsy type 1, H1N1, Pandemrix, Antibody, Prostaglandin, DP
Maria G. Belvisi - One of the best experts on this subject based on the ideXlab platform.
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Prostaglandin D2 and the role of the dp1 dp2 and tp Receptors in the control of airway reflex events
European Respiratory Journal, 2015Co-Authors: Sarah A Maher, Mark A Birrell, John J Adcock, Michael A Wortley, Eric Dubuis, Sara J Bonvini, Megan S Grace, Maria G. BelvisiAbstract:Prostaglandin D2 (PGD2) causes cough and levels are increased in asthma suggesting that it may contribute to symptoms. Although the Prostaglandin D2 Receptor 2 (DP2) is a target for numerous drug discovery programmes little is known about the actions of PGD2 on sensory nerves and cough. We used human and guinea pig bioassays, in vivo electrophysiology and a guinea pig conscious cough model to assess the effect of Prostaglandin D2 Receptor (DP1), DP2 and thromboxane Receptor antagonism on PGD2 responses. PGD2 caused cough in a conscious guinea pig model and an increase in calcium in airway jugular ganglia. Using pharmacology and Receptor-deficient mice we showed that the DP1 Receptor mediates sensory nerve activation in mouse, guinea pig and human vagal afferents. In vivo , PGD2 and a DP1 Receptor agonist, but not a DP2 Receptor agonist, activated single airway C-fibres. Interestingly, activation of DP2 inhibited sensory nerve firing to capsaicin in vitro and in vivo . The DP1 Receptor could be a therapeutic target for symptoms associated with asthma. Where endogenous PGD2 levels are elevated, loss of DP2 Receptor-mediated inhibition of sensory nerves may lead to an increase in vagally associated symptoms and the potential for such adverse effects should be investigated in clinical studies with DP2 antagonists. Prostaglandin D2 activates sensory nerves and evokes cough via DP1 Receptors
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Prostaglandin D2 and the role of the DP1, DP2 and TP Receptors in the control of airway reflex events
The European respiratory journal, 2014Co-Authors: Sarah A Maher, Mark A Birrell, John J Adcock, Michael A Wortley, Eric Dubuis, Sara J Bonvini, Megan S Grace, Maria G. BelvisiAbstract:Prostaglandin D2 (PGD2) causes cough and levels are increased in asthma suggesting that it may contribute to symptoms. Although the Prostaglandin D2 Receptor 2 (DP2) is a target for numerous drug discovery programmes little is known about the actions of PGD2 on sensory nerves and cough. We used human and guinea pig bioassays, in vivo electrophysiology and a guinea pig conscious cough model to assess the effect of Prostaglandin D2 Receptor (DP1), DP2 and thromboxane Receptor antagonism on PGD2 responses. PGD2 caused cough in a conscious guinea pig model and an increase in calcium in airway jugular ganglia. Using pharmacology and Receptor-deficient mice we showed that the DP1 Receptor mediates sensory nerve activation in mouse, guinea pig and human vagal afferents. In vivo, PGD2 and a DP1 Receptor agonist, but not a DP2 Receptor agonist, activated single airway C-fibres. Interestingly, activation of DP2 inhibited sensory nerve firing to capsaicin in vitro and in vivo. The DP1 Receptor could be a therapeutic target for symptoms associated with asthma. Where endogenous PGD2 levels are elevated, loss of DP2 Receptor-mediated inhibition of sensory nerves may lead to an increase in vagally associated symptoms and the potential for such adverse effects should be investigated in clinical studies with DP2 antagonists.
Trond Ulven - One of the best experts on this subject based on the ideXlab platform.
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synthesis and in vitro evaluation of a selective antagonist and the corresponding radioligand for the Prostaglandin D2 Receptor crth2
Bioorganic & Medicinal Chemistry Letters, 2007Co-Authors: Trond Ulven, Michael J Gallen, Mads Corvinius Nielsen, Nicole Merten, Carola Schmidt, Klaus Mohr, Christian Trankle, Evi KostenisAbstract:Abstract Synthesis and preliminary in vitro biological evaluation of a selective high-affinity CRTH2 antagonist is described. The stability of an N-benzyl group facilitated synthesis of the corresponding radioligand by tritiation of a brominated precursor. The compound [3H]TRQ11238 represents the first selective CRTH2 antagonist radioligand and exhibited a specific radioactivity of 52 Ci/mmol and a pKd of 9.0.
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the role of the Prostaglandin D2 Receptor dp in eosinophil trafficking
Journal of Immunology, 2007Co-Authors: Petra Schratl, Trond Ulven, Evi Kostenis, Julia F Royer, Eva M Sturm, Maria Waldhoer, Gerald Hoefler, Rufina Schuligoi, Irmgard Th Lippe, B A PeskarAbstract:Prostaglandin (PG) D2 is a major mast cell product that acts via two Receptors, the D-type prostanoid (DP) and the chemoattractant Receptor-homologous molecule expressed on Th2 cells (CRTH2) Receptors. Whereas CRTH2 mediates the chemotaxis of eosinophils, basophils, and Th2 lymphocytes, the role of DP has remained unclear. We report in this study that, in addition to CRTH2, the DP Receptor plays an important role in eosinophil trafficking. First, we investigated the release of eosinophils from bone marrow using the in situ perfused guinea pig hind limb preparation. PGD2 induced the rapid release of eosinophils from bone marrow and this effect was inhibited by either the DP Receptor antagonist BWA868c or the CRTH2 Receptor antagonist ramatroban. In contrast, BWA868c did not inhibit the release of bone marrow eosinophils when this was induced by the CRTH2-selective agonist 13,14-dihydro-15-keto-PGD2. In additional experiments, we isolated bone marrow eosinophils from the femoral cavity and found that these cells migrated toward PGD2. We also observed that BWA868c inhibited this response to a similar extent as ramatroban. Finally, using immunohistochemistry we could demonstrate that eosinophils in human bone marrow specimens expressed DP and CRTH2 Receptors at similar levels. Eosinophils isolated from human peripheral blood likewise expressed DP Receptor protein but at lower levels than CRTH2. In agreement with this, the chemotaxis of human peripheral blood eosinophils was inhibited both by BWA868c and ramatroban. These findings suggest that DP Receptors comediate with CRTH2 the mobilization of eosinophils from bone marrow and their chemotaxis, which might provide the rationale for DP antagonists in the treatment of allergic disease.
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antagonism of the Prostaglandin D2 Receptor crth2 attenuates asthma pathology in mouse eosinophilic airway inflammation
Respiratory Research, 2007Co-Authors: Lena Uller, Lisa Alenmyr, Magnus Korsgren, Trond Ulven, Thomas Hogberg, Gunnar Andersson, Carl G A Persson, Jesper Mosolff Mathiesen, Evi KostenisAbstract:Background Mast cell-derived Prostaglandin D2 (PGD2), may contribute to eosinophilic inflammation and mucus production in allergic asthma. Chemoattractant Receptor homologous molecule expressed on TH2 cells (CRTH2), a high affinity Receptor for Prostaglandin D2, mediates trafficking of TH2-cells, mast cells, and eosinophils to inflammatory sites, and has recently attracted interest as target for treatment of allergic airway diseases. The present study involving mice explores the specificity of CRTH2 antagonism of TM30089, which is structurally closely related to the dual TP/CRTH2 antagonist ramatroban, and compares the ability of ramatroban and TM30089 to inhibit asthma-like pathology.
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on the mechanism of interaction of potent surmountable and insurmountable antagonists with the Prostaglandin D2 Receptor crth2
Molecular Pharmacology, 2006Co-Authors: Jesper Mosolff Mathiesen, Trond Ulven, Julia F Royer, Arthur Christopoulos, Mercedes Campillo, Akos Heinemann, Leonardo Pardo, Evi KostenisAbstract:Chemoattractant Receptor-homologous molecule expressed on T helper 2 cells (CRTH2) has attracted interest as a potential therapeutic target in inflammatory diseases. Ramatroban, a thromboxane A2 Receptor antagonist with clinical efficacy in allergic rhinitis, was recently found to also display potent CRTH2 antagonistic activity. Here, we present the pharmacological profile of three ramatroban analogs that differ chemically from ramatroban by either a single additional methyl group (TM30642), or an acetic acid instead of a propionic acid side chain (TM30643), or both modifications (TM30089). All three compounds bound to human CRTH2 stably expressed in human embryonic kidney 293 cells with nanomolar affinity. [3H]Prostaglandin D2 (PGD2) saturation analysis reveals that ramatroban and TM30642 decrease PGD2 affinity, whereas TM30643 and TM30089 exclusively depress ligand binding capacity ( B max). Each of the three compounds acted as potent CRTH2 antagonists, yet the nature of their antagonism differed markedly. In functional assays measuring inhibition of PGD2-mediated 1) guanosine 5′- O -(3-thio)triphosphate binding, 2) β-arrestin translocation, and 3) shape change of human eosinophils endogenously expressing CRTH2, ramatroban, and TM30642 produced surmountable antagonism and parallel rightward shifts of the PGD2 concentration-response curves. For TM30643 and TM30089, this shift was accompanied by a progressive reduction of maximal response. Binding analyses indicated that the functional insurmountability of TM30643 and TM30089 was probably related to long-lasting CRTH2 inhibition mediated via the orthosteric site of the Receptor. A mechanistic understanding of insurmountability of CRTH2 antagonists could be fundamental for development of this novel class of anti-inflammatory drugs.
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On the mechanism of interaction of potent surmountable and insurmountable antagonists with the Prostaglandin D2 Receptor CRTH2.
Molecular pharmacology, 2006Co-Authors: Jesper Mosolff Mathiesen, Trond Ulven, Julia F Royer, Arthur Christopoulos, Mercedes Campillo, Akos Heinemann, Leonardo Pardo, Evi KostenisAbstract:Chemoattractant Receptor-homologous molecule expressed on T helper 2 cells (CRTH2) has attracted interest as a potential therapeutic target in inflammatory diseases. Ramatroban, a thromboxane A2 Receptor antagonist with clinical efficacy in allergic rhinitis, was recently found to also display potent CRTH2 antagonistic activity. Here, we present the pharmacological profile of three ramatroban analogs that differ chemically from ramatroban by either a single additional methyl group (TM30642), or an acetic acid instead of a propionic acid side chain (TM30643), or both modifications (TM30089). All three compounds bound to human CRTH2 stably expressed in human embryonic kidney 293 cells with nanomolar affinity. [3H]Prostaglandin D2 (PGD2) saturation analysis reveals that ramatroban and TM30642 decrease PGD2 affinity, whereas TM30643 and TM30089 exclusively depress ligand binding capacity (Bmax). Each of the three compounds acted as potent CRTH2 antagonists, yet the nature of their antagonism differed markedly. In functional assays measuring inhibition of PGD2-mediated 1) guanosine 5'-O-(3-thio)triphosphate binding, 2) beta-arrestin translocation, and 3) shape change of human eosinophils endogenously expressing CRTH2, ramatroban, and TM30642 produced surmountable antagonism and parallel rightward shifts of the PGD2 concentration-response curves. For TM30643 and TM30089, this shift was accompanied by a progressive reduction of maximal response. Binding analyses indicated that the functional insurmountability of TM30643 and TM30089 was probably related to long-lasting CRTH2 inhibition mediated via the orthosteric site of the Receptor. A mechanistic understanding of insurmountability of CRTH2 antagonists could be fundamental for development of this novel class of anti-inflammatory drugs.
