16 results on '"Defrêne, E"'
Search Results
2. Synthesis and pharmacological evaluation of dimer derivatives of the bradykinin receptor antagonist HOE-140
- Author
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Daffix, I., primary, Amblard, M., additional, Bergé, G., additional, Dodey, P., additional, Pruneau, D., additional, Paquet, J.-L., additional, Fouchet, C., additional, Franck, R.-M., additional, Defrêne, E., additional, Luccarini, J.-M., additional, Bélichard, P., additional, and Martinez, J., additional
- Published
- 2009
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3. Pharmacological and molecular evidence for kinin B1 receptor expression in urinary bladder of cyclophosphamide-treated rats
- Author
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Belichard, P, primary, Luccarini, J M, additional, Defrêne, E, additional, Faye, P, additional, Franck, R M, additional, Duclos, H, additional, Paquet, J L, additional, and Pruneau, D, additional
- Published
- 1999
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4. Pharmacological characterization of the bradykinin B2receptor: inter-species variability and dissociation between binding and functional responses
- Author
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Paquet, J -L, primary, Luccarini, J -M, additional, Fouchet, C, additional, Defrêne, E, additional, Loillier, B, additional, Robert, C, additional, Bélichard, P, additional, Cremers, B, additional, and Pruneau, D, additional
- Published
- 1999
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- View/download PDF
5. Pharmacological evidence for a single bradykinin B2 receptor in the guinea-pig
- Author
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Pruneau, D., primary, Luccarini, J.M., additional, Defrêne, E., additional, Paquet, J.L., additional, and Bélichard, P., additional
- Published
- 1995
- Full Text
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6. Pharmacological and molecular evidence for kinin B1 receptor expression in urinary bladder of cyclophosphamide-treated rats.
- Author
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Belichard, P, Luccarini, J M, Defrêne, E, Faye, P, Franck, R M, Duclos, H, Paquet, J L, and Pruneau, D
- Published
- 1999
- Full Text
- View/download PDF
7. Pharmacological characterization of the bradykinin B2 receptor: inter-species variability and dissociation between binding and functional responses.
- Author
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Paquet, J -L, Luccarini, J -M, Fouchet, C, Defrêne, E, Loillier, B, Robert, C, Bélichard, P, Cremers, B, and Pruneau, D
- Published
- 1999
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- View/download PDF
8. Pharmacological and molecular evidence for kinin B1receptor expression in urinary bladder of cyclophosphamide‐treated rats
- Author
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Belichard, P, Luccarini, J M, Defrêne, E, Faye, P, Franck, R M, Duclos, H, Paquet, J L, and Pruneau, D
- Abstract
In the present study, we developed an experimental model of cystitis induced by cyclophosphamide (CYP). In order to characterize des‐Arg9‐BK‐induced contraction on the urinary bladder (UB) during the development of inflammation and to quantify kinin B1receptor gene expression using a quantitative RT–PCR technique.In the presence of peptidase inhibitors captopril (10 μM), DL‐thiorphan (1 μM) and DL‐2‐mercaptomethyl‐3‐guanidino‐ethylthiopropanoic acid (MERGEPTA 5 μM), bradykinin (BK) (0.3–3,000 nM) evoked a concentration‐dependent contraction of rat UB which was not different between the CYP‐ and vehicle‐treated groups. Unlike BK, des‐Arg9‐BK (0.3–100,000 nM) did not contract UB from vehicle‐treated rats but contracted vigorously bladder strips from CYP‐treated rats 14, 24 and 168 h after treatment. In UB of 24 h treated rat, the pD2value of des‐Arg9‐BK was 7.3±0.1.The cyclo‐oxygenase inhibitor indomethacin (3 μM) reduced by 30% the maximal response of des‐Arg9‐BK. Both the kinin B1receptor antagonists des‐Arg9‐[Leu8]BK (10 μM) and des‐Arg10‐Hoe 140 (10 μM) produced a rightward shift of the concentration‐response curve to des‐Arg9‐BK yielding pKBvalues of 6.8±0.2 and 7.2±0.1, respectively, whilst the kinin B2receptor antagonist Hoe 140 (1 μM) had no effect.After CYP treatment, mRNA coding for the kinin B1receptor appeared predominantly in UB. In this organ, the induction was progressive, reaching a maximum 48 h after CYP treatment.In conclusion, the present study provides strong evidence for an induction of kinin B1receptors in UB of CYP‐treated rats. This was associated at a molecular level with an increase in mRNA expression of the gene coding for the kinin B1receptor. This kinin receptor displayed the whole features of a classical rat kinin B1receptor.
- Published
- 1999
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9. Pharmacological evidence for a single bradykinin B2receptor in the guinea‐pig
- Author
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Pruneau, D., Luccarini, J.M., Defrêne, E., Paquet, J.L., and Bélichard, P.
- Abstract
1The present study addresses the possibility of the existence of different kinin B2receptor subtypes in the guinea‐pig by evaluating the affinity of peptide and nonpeptide receptor antagonists. For this purpose, jugular vein rings, ileum segments, lung parenchymal and trachea strips were set up in organ baths for isometric tension measurements. The experiments were conducted in the presence of indomethacin (3 μm), atropine (10 μm) and captopril (10 μm).2BK contracted jugular vein (JV), ileum (GPI), parenchyma (LP) and trachea (GPT) with an EC50of 13.2 ± 1.4 nM (n= 27), 11.2 + 2.1 (n= 26), 23.6 ± 6.3 nM (n= 26) and 33.0 ± 6.5 (n= 27), respectively. Thiorphan, a neutral endopeptidase (EC 3.4.24.11) inhibitor and MERGETPA (DL‐2‐mercaptomethyl‐3‐guanidinoethylthiopropanoic acid), a carboxypeptidase inhibitor, had no effect on the BK‐induced contractions of JV, GPI and LP. In the GPT, thiorpan potentiated the contractile response to BK and was thus added in the corresponding experiments.3The peptide B2receptor antagonist, Hoe 140 and the nonpeptide compound, WIN 64338, behaved as noncompetitive antagonists against contractile responses to cumulative BK in the four tissues although Hoe 140 appeared as a competitive inhibitor in the GPT only. In order to compare the inhibitory potency of these compounds between tissues, pKBvalues were determined. Mean values of pKBfor Hoe 140 were 8.05 ± 0.07, 8.43 ± 0.11, 8.13 ± 0.18 and 8.52 ± 0.25 in the JV, GPI, GPT and LP, respectively. WIN 64338 gave mean pKBvalues of 6.89 ± 0.10, 7.57 ± 0.12, 7.36±0.12 and 7.51 ± 0.28 in the JV, GPI, LP and GPT, respectively.4D‐Arg [Hyp3, D‐Phe7, Leu8]BK and D‐Arg [Hyp3, D‐Phe7]BK (NPC 567) inhibited in a competitive fashion the concentration‐response curves to BK. Values of pA2for each compound were not significantly different in the four tissues and were between 5.81 and 6.31 for D‐Arg [Hyp3, D‐Phe7, Leu8]BK and between 5.55 and 5.65 for NPC 567.5We conclude that the contractile response to BK in guinea‐pig vascular, intestine and lung tissue is mediated by a unique B2receptor. Thus, our results do not support the existence of a B3receptor in the trachea and we suggest that the previously reported B2Breceptor subtype simply represents the guinea‐pig isoform. The present study addresses the possibility of the existence of different kinin B2receptor subtypes in the guinea‐pig by evaluating the affinity of peptide and nonpeptide receptor antagonists. For this purpose, jugular vein rings, ileum segments, lung parenchymal and trachea strips were set up in organ baths for isometric tension measurements. The experiments were conducted in the presence of indomethacin (3 μm), atropine (10 μm) and captopril (10 μm). BK contracted jugular vein (JV), ileum (GPI), parenchyma (LP) and trachea (GPT) with an EC50of 13.2 ± 1.4 nM (n= 27), 11.2 + 2.1 (n= 26), 23.6 ± 6.3 nM (n= 26) and 33.0 ± 6.5 (n= 27), respectively. Thiorphan, a neutral endopeptidase (EC 3.4.24.11) inhibitor and MERGETPA (DL‐2‐mercaptomethyl‐3‐guanidinoethylthiopropanoic acid), a carboxypeptidase inhibitor, had no effect on the BK‐induced contractions of JV, GPI and LP. In the GPT, thiorpan potentiated the contractile response to BK and was thus added in the corresponding experiments. The peptide B2receptor antagonist, Hoe 140 and the nonpeptide compound, WIN 64338, behaved as noncompetitive antagonists against contractile responses to cumulative BK in the four tissues although Hoe 140 appeared as a competitive inhibitor in the GPT only. In order to compare the inhibitory potency of these compounds between tissues, pKBvalues were determined. Mean values of pKBfor Hoe 140 were 8.05 ± 0.07, 8.43 ± 0.11, 8.13 ± 0.18 and 8.52 ± 0.25 in the JV, GPI, GPT and LP, respectively. WIN 64338 gave mean pKBvalues of 6.89 ± 0.10, 7.57 ± 0.12, 7.36±0.12 and 7.51 ± 0.28 in the JV, GPI, LP and GPT, respectively. D‐Arg [Hyp3, D‐Phe7, Leu8]BK and D‐Arg [Hyp3, D‐Phe7]BK (NPC 567) inhibited in a competitive fashion the concentration‐response curves to BK. Values of pA2for each compound were not significantly different in the four tissues and were between 5.81 and 6.31 for D‐Arg [Hyp3, D‐Phe7, Leu8]BK and between 5.55 and 5.65 for NPC 567. We conclude that the contractile response to BK in guinea‐pig vascular, intestine and lung tissue is mediated by a unique B2receptor. Thus, our results do not support the existence of a B3receptor in the trachea and we suggest that the previously reported B2Breceptor subtype simply represents the guinea‐pig isoform.
- Published
- 1995
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10. Differential effects of selective- and pan-PPAR agonists on experimental steatohepatitis and hepatic macrophages ☆ .
- Author
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Lefere S, Puengel T, Hundertmark J, Penners C, Frank AK, Guillot A, de Muynck K, Heymann F, Adarbes V, Defrêne E, Estivalet C, Geerts A, Devisscher L, Wettstein G, and Tacke F
- Subjects
- Animals, Male, Mice, Disease Models, Animal, Disease Progression, Dose-Response Relationship, Drug, Hypolipidemic Agents pharmacology, Liver Cirrhosis etiology, Liver Cirrhosis pathology, Liver Cirrhosis prevention & control, Fatty Liver chemically induced, Fatty Liver drug therapy, Fatty Liver pathology, Fenofibrate pharmacology, Liver drug effects, Liver pathology, Macrophages drug effects, Macrophages pathology, Peroxisome Proliferator-Activated Receptors agonists, Thiazoles pharmacology
- Abstract
Background & Aims: Peroxisome proliferator-activated receptors (PPARs) are essential regulators of whole-body metabolism, but also modulate inflammation in immune cells, notably macrophages. We compared the effects of selective PPAR agonists to those of the pan-PPAR agonist lanifibranor in non-alcoholic fatty liver disease (NAFLD), and studied isoform-specific effects on hepatic macrophage biology., Methods: Lanifibranor or selective PPARα (fenofibrate), PPARγ (pioglitazone) and PPARδ (GW501516) agonists were therapeutically administered in choline-deficient, amino acid-defined high-fat diet (CDAA-HFD)- and Western diet (WD)-fed mouse models of NAFLD. Acute liver injury was induced by carbon tetrachloride (CCl
4 ). The role of PPARs on macrophage functionality was studied in isolated hepatic macrophages, bone marrow-derived macrophages stimulated with palmitic acid, and circulating monocytes from patients with NAFLD., Results: Lanifibranor improved all histological features of steatohepatitis in CDAA-HFD-fed mice, including liver fibrosis, thereby combining and exceeding specific effects of the single PPAR agonists. Its potent anti-steatotic efficacy was confirmed in a 3D liver biochip model with primary cells. Infiltrating hepatic monocyte-derived macrophages were reduced following PPAR agonist administration, especially with lanifibranor, even after short-term treatment, paralleling improved steatosis and hepatitis. Lanifibranor similarly decreased steatosis, liver injury and monocyte infiltration in the WD model. In the acute CCl4 model, neither single nor pan-PPAR agonists directly affected monocyte recruitment. Hepatic macrophages isolated from WD-fed mice displayed a metabolically activated phenotype. Lanifibranor attenuated the accompanying inflammatory activation in both murine palmitic acid-stimulated bone marrow-derived macrophages, as well as patient-derived circulating monocytes, in a PPARδ-dependent fashion., Conclusion: Pan-PPAR agonists combine the beneficial effects of selective PPAR agonists and may counteract inflammation and disease progression more potently. PPARδ agonism and lanifibranor directly modulate macrophage activation, but not infiltration, thereby synergizing with beneficial metabolic effects of PPARα/γ agonists., Lay Summary: Peroxisome proliferated-activated receptors (PPARs) are essential regulators of metabolism and inflammation. We demonstrated that the pan-PPAR agonist lanifibranor ameliorated all aspects of non-alcoholic fatty liver disease in independent experimental mouse models. Non-alcoholic fatty liver disease and fatty acids induce a specific polarization status in macrophages, which was altered by lanifibranor to increase expression of lipid handling genes, thereby decreasing inflammation. PPAR isoforms have differential therapeutic effects on fat-laden hepatocytes, activated hepatic stellate cells and inflammatory macrophages, supporting the clinical development of pan-PPAR agonists., Competing Interests: Conflict of interest VA, ED, CE and GW are employees of Inventiva. Work in FT's laboratory has received funding by Allergan, Galapagos, Inventiva and Bristol Myers Squibb. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)- Published
- 2020
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11. The new-generation pan-peroxisome proliferator-activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis.
- Author
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Wettstein G, Luccarini JM, Poekes L, Faye P, Kupkowski F, Adarbes V, Defrêne E, Estivalet C, Gawronski X, Jantzen I, Philippot A, Tessier J, Tuyaa-Boustugue P, Oakley F, Mann DA, Leclercq I, Francque S, Konstantinova I, Broqua P, and Junien JL
- Abstract
IVA337 is a pan-peroxisome proliferator-activated receptor (PPAR) agonist with moderate and well-balanced activity on the three PPAR isoforms (α, γ, δ). PPARs are regulators of lipid metabolism, inflammation, insulin resistance, and fibrogenesis. Different single or dual PPAR agonists have been investigated for their therapeutic potential in nonalcoholic steatohepatitis (NASH), a chronic liver condition in which steatosis coexists with necroinflammation, potentially leading to liver fibrosis and cirrhosis. Clinical results have demonstrated variable improvements of histologically assessed hepatic lesions depending on the profile of the tested drug, suggesting that concomitant activation of the three PPAR isoforms would translate into a more substantial therapeutic outcome in patients with NASH. We investigated the effects of IVA337 on several preclinical models reproducing the main metabolic and hepatic features associated with NASH. These models comprised a diet-induced obesity model (high-fat/high-sucrose diet); a methionine- and choline-deficient diet; the foz/foz model; the CCl
4 -induced liver fibrosis model (prophylactic and therapeutic) and human primary hepatic stellate cells. IVA337 normalized insulin sensitivity while controlling body weight gain, adiposity index, and serum triglyceride increases; it decreased liver steatosis, inflammation, and ballooning. IVA337 demonstrated preventive and curative effects on fibrosis in the CCl4 model and inhibited proliferation and activation of human hepatic stellate cells, the key cells driving liver fibrogenesis in NASH. Moreover, IVA337 inhibited the expression of (pro)fibrotic and inflammasome genes while increasing the expression of β-oxidation-related and fatty acid desaturation-related genes in both the methionine- and choline-deficient diet and the foz/foz model. For all models, IVA337 displayed an antifibrotic efficacy superior to selective PPARα, PPARδ, or PPARγ agonists. Conclusion : The therapeutic potential of IVA337 for the treatment of patients with NASH is supported by our data. ( Hepatology Communications 2017;1:524-537).- Published
- 2017
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12. Pharmacological profile of LF 16-0687, a new potent non-peptide bradykinin B2 receptor antagonist.
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Pruneau D, Paquet JL, Luccarini JM, Defrêne E, Fouchet C, Franck RM, Loillier B, Robert C, Bélichard P, Duclos H, Cremers B, and Dodey P
- Subjects
- Animals, Blood Pressure drug effects, Blood-Brain Barrier, Cricetinae, Dose-Response Relationship, Drug, Humans, In Vitro Techniques, Inositol Phosphates metabolism, Male, Muscle Contraction drug effects, Rats, Rats, Sprague-Dawley, Receptor, Bradykinin B2, Bradykinin Receptor Antagonists, Quinolines pharmacology
- Abstract
LF 16-0687 (1-[[2,4-dichloro-3-[[(2,4-dimethylquinolin-8-yl)oxy] methyl]phenyl]sulfonyl]-N-[3-[[4-(aminoimethyl) phenyl] carbonylamino]propyl]-2(S)-pyrrolidinecarboxamide) has been selected from a large-scale medicinal chemistry program for further development. In competition binding studies using [3H]bradykinin (BK), LF 16-0687 bound to the human, rat and guinea-pig recombinant B2 receptor expressed in CHO cells giving K(i) values of 0.67 nM, 1.74 nM and 1.37 nM, respectively. It also bound to the native BK B2 receptor from human umbilical vein (HUV), rat uterus (RU) and guinea-pig ileum (GPI) giving K(i) values of 0.89 nM, 0.28 nM and 0.98 nM, respectively. It inhibited BK-induced IP1, IP2 and IP3 formation in INT407 cells yielding pK(B) values of 8.5, 8.6 and 8.7, respectively. In isolated organs experiments, LF 16-0687 behaved as a competitive antagonist of BK-mediated contractions giving pA2 values of 9.1 in HUV, 7.7 in RU and 9.1 in GPI. Binding and functional studies performed over 40 different receptors revealed that LF 16-0687 was selective for the BK B2 receptor. A continuous intravenous infusion of LF 16-0687 antagonized in a dose-dependent manner and with a rapid onset of action BK-induced hypotensive response. Subcutaneous administration of LF 16-0687 at 1.1 micromol/kg to rats markedly reduced BK-induced edema of the stomach (- 69%), duodenum (-65%) and pancreas (-56%).
- Published
- 1999
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13. Pharmacological characterization of the bradykinin B2 receptor: inter-species variability and dissociation between binding and functional responses.
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Paquet JL, Luccarini JM, Fouchet C, Defrêne E, Loillier B, Robert C, Bélichard P, Cremers B, and Pruneau D
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- Animals, Binding, Competitive, Bradykinin metabolism, Bradykinin pharmacology, Bradykinin Receptor Antagonists, CHO Cells, Cricetinae, Humans, Inositol Phosphates, Peptides metabolism, Rats, Receptor, Bradykinin B2, Species Specificity, Tromethamine analogs & derivatives, Umbilical Veins drug effects, Umbilical Veins physiology, Vasoconstriction drug effects, Adrenergic beta-Antagonists pharmacology, Bradykinin analogs & derivatives, Receptors, Bradykinin metabolism
- Abstract
1. The present study addresses the differences in binding profiles and functional properties of the human and rat bradykinin (BK) B2 receptor using various kinin receptor peptide derivatives as well as the non-peptide receptor antagonists WIN 64338 (phosphonium, [[4-[[2-[[bis(cyclohexylamino)methylene]amino]-3-(2-naphtalenyl)1- oxopropyl]amino]-phenyl]-methyl]tributyl, chloride, monohydro-chloride), and FR173657 (E)-3-(6-acetamido-3-pyridyl)-N-[-N-[2,4-dichloro-3-[(2-methyl-8-quinoli nyl)oxymethyl]-phenyl]N-methylamino carbonyl methyl] acrylamide. 2. [3H]-BK bound with a similar affinity to membranes of Chinese hamster ovary cells (CHO-K1) expressing the cloned human (hB2-CHO) or rat (rB2-CHO) B2 receptor, human embryonic intestine cells (INT407) expressing the native B2 receptor, human umbilical vein (HUV) and rat uterus (RU). WIN 64338 and FR173657 bound with a 3.8-6.6 fold and 7.0-16.3 fold higher affinity the rat than the human B2 receptor, respectively. The affinity values of BK derivatives as well as non-peptide antagonists were reduced by 6-23 fold in physiological HBSS compared to low ionic strength TES binding buffer. 3. BK (0.01-3000 nM) increased inositol triphosphates (IP3) levels in hB2-CHO, rB2-CHO and INT407 cells. The B2 receptor antagonist, Hoe 140 (D-Arg0-[ Hyp3, Thi5, D-Tic7, Oic8]-BK) at 10(-7) M, significantly shifted to the right the IP3 response curves to BK giving apparent pKB values of 8.56, 9.79 and 8.84 for hB2-CHO, rB2-CHO and INT407 cells, respectively. 4. In human isolated umbilical vein, Hoe 140, D-Arg0-[Hyp3, D-Phe7, Leu8]-BK and NPC 567 had a lower potency in functional assays (pKB 8.18, 5.77 and 5.60, respectively) than expected from their affinity in binding studies (pKi 10.52, 8.64 and 8.27, respectively). 5. FR173657 behaved as a high affinity ligand with pKi values of 8.59 and 9.81 and potent competitive antagonist with pKB values of 7.80 and 8.17 in HUV and RU, respectively. FR173657 bound with a similar affinity the cloned and native bradykinin B2 receptor in human (pKi of 8.66 and 8.59, respectively) and in rat (pKi 9.67 and 9.81, respectively). 6. In conclusion, we suggest that the binding buffer composition has to be taken into account when screening new compounds and that inter-species differences should be considered when setting up animal models with the aim of developing bradykinin B2 receptor antagonists as therapeutic agents.
- Published
- 1999
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14. In vitro and in vivo effects of the new nonpeptide bradykinin B2 receptor antagonist, LF 16-0335C, on guinea-pig and rat kinin receptors.
- Author
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Pruneau D, Luccarini JM, Fouchet C, Defrêne E, Franck RM, Loillier B, Duclos H, Robert C, Cremers B, Bélichard P, and Paquet JL
- Subjects
- Acetylcholine pharmacology, Animals, Binding, Competitive, Blood Pressure drug effects, Bradykinin metabolism, Bradykinin pharmacology, Dose-Response Relationship, Drug, Female, Guinea Pigs, Histamine pharmacology, Ileum drug effects, Ileum physiology, In Vitro Techniques, Male, Muscle Contraction drug effects, Rats, Receptor, Bradykinin B2, Receptors, Bradykinin metabolism, Tritium, Uterus drug effects, Uterus physiology, Vasodilator Agents pharmacology, Amidines pharmacology, Bradykinin Receptor Antagonists, Piperazines pharmacology
- Abstract
Activation of the kinin-kallikrein system and stimulation of bradykinin (BK) B2 receptors are thought to play an important role in the pathophysiology of inflammation and pain. In the present study, we report the pharmacological properties of a novel nonpeptide bradykinin B2 receptor antagonist, LF 16-0335C, (1-[[3-[(2,4-dimethylquinolin-8-yl) oxymethyl]-2,4-dichloro-phenyl]sulfonyl]-2(S)-[[4-[4- (aminoiminomethyl)-phenylcarbonyl]piperazin-1-yl]carbo nyl]pyrrolidine, 2HCl). In binding studies, LF 16-0335C competed with [3H]bradykinin giving Ki values of 1.65 +/- 0.36 nM and 2.20 +/- 0.30 nM in membrane preparations from rat uterus (RU) and guinea-pig ileum (GPI), respectively. In functional experiments, LF 16-0335C inhibited in a competitive manner BK-induced contractions of both isolated RU and GPI, leading to calculated pA2 values of 7.70 +/- 0.70 and 8.30 +/- 0.30, respectively. The inhibitory effect of LF 16-0335C was fully reversible by washing in the guinea-pig ileum. In vivo, LF 16-0335C given intravenously inhibited in a dose-dependent manner BK-induced hypotension in both animal species, although it was more potent in the guinea-pig than in the rat (ED50, 2.5 +/- 1.6 micrograms/kg versus 22.6 +/- 2.3 micrograms/kg). BK is a potent constrictor of guinea-pig airways and this effect was markedly attenuated by LF 16-0335C. In contrast, LF 16-0335C did not affect histamine- and acetylcholine-induced hypotensive response in the rat. We conclude that LF 16-0335C is a potent and selective nonpeptide B2 receptor antagonist which equally binds to the rat and guinea-pig receptor but displays a different in vivo potency in the two species. Therefore, this drug represents a useful tool to better assess the role of bradykinin in pathophysiological conditions.
- Published
- 1999
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15. LF 16.0335, a novel potent and selective nonpeptide antagonist of the human bradykinin B2 receptor.
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Pruneau D, Luccarini JM, Fouchet C, Defrêne E, Franck RM, Loillier B, Duclos H, Robert C, Cremers B, Bélichard P, and Paquet JL
- Subjects
- Amidines chemistry, Binding, Competitive, Cells, Cultured, Dose-Response Relationship, Drug, Humans, In Vitro Techniques, Phosphatidylinositols biosynthesis, Piperazines chemistry, Receptor, Bradykinin B2, Umbilical Veins drug effects, Umbilical Veins metabolism, Vasoconstriction drug effects, Amidines pharmacology, Bradykinin pharmacology, Bradykinin Receptor Antagonists, Piperazines pharmacology
- Abstract
1. In the present paper, we describe the in vitro pharmacological properties of LF 16.0335 (1-[[3-[(2,4-dimethylquinolin-8-yl)oxymethyl]-2,4-dichloro-p henyl]sulphonyl] -2(S) - [[4 -[4-(aminoiminomethyl)phenylcarbonyl]piperazin-1-yl]ca rbonyl]pyrrolidine), a novel and potent nonpeptide antagonist of the human bradykinin (BK) B2 receptor. 2. LF 16.0335 displaced [3H]-BK binding to membrane preparations from CHO cells expressing the cloned human B2 receptor, INT 407 cells and human umbilical vein with Ki values of 0.84+/-0.39 nM, 1.26+/-0.68 nM and 2.34+/-0.36 nM, respectively. 3. In saturation binding studies performed in INT 407 cell membranes in the presence or absence of LF 16.0335, max values of [3H]-BK were not significantly changed suggesting that LF 16.0335 behaves as a competitive antagonist. 4. LF 16.0335 had no affinity for the cloned human kinin B1 receptor stably expressed in 293 cells. In addition, this compound at 1 microM did not significantly bind to a range of 40 different membrane receptors and eight ion channels except muscarinic M2 and M1 receptors for which an IC50 value of 0.9 and 1 microM was obtained. 5. BK stimulates in a concentration-dependent manner phosphoinositosides (IPs) production in cultured INT 407 cells. Concentration-response-curves to BK were shifted to the right in the presence of LF 16.0335 (0.1 microM) without reduction of the maximum. LF 16.0335 inhibited the concentration-contraction curve to BK in the human umbilical vein giving a pA2 value of 8.30+/-0.30 with a Schild plot slope that was not different from unity. 6. These results demonstrate that LF 16.0335 is a potent, selective and competitive antagonist of the human bradykinin B2 receptor.
- Published
- 1998
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16. Characterisation of bradykinin receptors from juvenile pig coronary artery.
- Author
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Pruneau D, Luccarini JM, Defrêne E, Paquet JL, and Bélichard P
- Subjects
- Animals, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Bradykinin analogs & derivatives, Bradykinin pharmacology, Bradykinin Receptor Antagonists, Coronary Vessels drug effects, Endothelium, Vascular drug effects, Endothelium, Vascular metabolism, In Vitro Techniques, Indomethacin pharmacology, Kinetics, Male, Muscle Relaxation drug effects, Muscle, Smooth, Vascular drug effects, Swine, Coronary Vessels metabolism, Muscle, Smooth, Vascular metabolism, Receptors, Bradykinin metabolism
- Abstract
Coronary artery rings from juvenile male farm pigs were incubated for 6 h and precontracted with U46619. The rings relaxed in response to des-Arg9-bradykinin (pD2, 7.78 +/- 0.13; Emax, 87.4 +/- 4.3%) and to bradykinin (pD2, 8.69 +/- 0.30; Emax, 104.2 +/- 4.4%). These responses were abolished by endothelium removal and unaffected by indomethacin whilst NG-nitro-L-arginine reduced the relaxation due to des-Arg9-bradykinin only. Preincubation with cycloheximide or actinomycin had no effect against relaxations mediated by kinins whilst the protein trafficking inhibitor, brefeldin A, reduced by 52% the maximum response to des-Arg9-bradykinin. The bradykinin receptor antagonists, des-Arg9-[Leu8]bradykinin, Hoe 140 (D-Arg-[Hyp3, Thi5, D-Tic7, Oic8]bradykinin) and NPC 567 (D-Arg-[Hyp3,D-Phe7]bradykinin) antagonized competitively the response to des-Arg9-bradykinin, giving respective pA2 values of 6.82 +/- 0.34, 6.63 +/- 0.28 and 6.48 +/- 0.41 whereas the non-peptide bradykinin B2 receptor antagonist, WIN 64338 (phosphonium, [[4-[[2-[[bis(cyclohexylamino)methylene]amino]-3-(2- naphtalenyl) 1-oxopropyl]amino]-phenyl]-methyl]tributyl chloride, monohydrochloride), was inactive. Hoe 140 and WIN 64338 but not des-Arg9[Leu8]bradykinin behaved as competitive antagonists towards the relaxation due to bradykinin. In conclusion, both bradykinin B2 and B1 receptors are present on the endothelium of large coronary arteries from juvenile pig. The bradykinin B1 receptor subtype appears partly inducible and is coupled to the synthesis of nitric oxide.
- Published
- 1996
- Full Text
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