DOCSLIB.ORG

A New Family of Thromboxane Receptor Antagonists with Secondary Thromboxane Synthase Inhibition

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A New Family of Thromboxane Receptor Antagonists with Secondary Thromboxane Synthase Inhibition 0022-3565/02/3012-618–624$7.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 301, No. 2 Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics 4765/979886 JPET 301:618–624, 2002 Printed in U.S.A. A New Family of Thromboxane Receptor Antagonists with Secondary Thromboxane Synthase Inhibition CECIL R. PACE-ASCIAK,1 DENIS REYNAUD, PETER DEMIN, RUKSHANA ASLAM, and ANDREA SUN Programme in Integrative Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada Received November 16, 2001; accepted January 18, 2002 This article is available online at http://jpet.aspetjournals.org ABSTRACT ϭ ϫ We report herein a novel class of thromboxane receptor (TP formation and aggregation evoked by collagen with an IC50 8 receptor) antagonists modeled on unstable natural lipids that we 10Ϫ7 M. Other PBT (hepoxilin cyclopropane) analogs so far tested identified several years ago, the hepoxilins. These antagonists were 5- to 10-fold less active, and the native hepoxilins were have been rendered chemically and biologically more stable than about 500-fold less active. Neither PBT-3 nor the other analogs the natural compounds through structural modification by chem- inhibited 12-lipoxygenase, phospholipase A2, or cyclooxygenase ical synthesis. We demonstrate that the analogs inhibit the aggre- 1 or 2, and weakly stimulated adenyl cyclase (threshold stimula- gation of human platelets in vitro evoked by the thromboxane tion at 10Ϫ7 M and little selectivity for each of the PBT com- receptor agonists, I-BOP ([1S-[1␣,2␣(Z),3␤(1E,3S*),4␣]]-7-[3-[3- pounds). TP antagonism by PBT-3 was further demonstrated in 125 hydroxy-4-(4-iodophenoxy)-1-butenyl]-7-oxabi-cyclo[2.2.1]hept- receptor binding studies through use of I-BOP, where the IC50 2-yl]5-heptenoic acid) and U46619 (9,11-dideoxy-9␣,11␣- for PBT-3 was 8 ϫ 10Ϫ9 M, approximately 16-fold less than for methanoepoxy-prosta-5Z,13E-dien-1-oic acid). The most potent I-BOP itself. These findings identify a new mode of action of of the analogs described, PBT-3 [10(S)-hydroxy-11,12-cyclopro- PBT-3 and other related analogs as primarily TP antagonists. pyl-eicosa-5Z,8Z,14Z-trienoic acid methyl ester], has an IC50 ver- These studies identify a new family of compounds useful in further sus aggregation by I-BOP ϭ 0.6 ϫ 10Ϫ7 M and versus U46619 ϭ development as novel therapeutics for thromboxane-mediated 7 ϫ 10Ϫ7 M, representing one of the most potent anti-aggregating diseases. substances so far described. PBT-3 also inhibits thromboxane Platelet aggregation is an important component of the diate, prostaglandin endoperoxide, common to all the hemostatic mechanism that prevents undesired bleeding, in prostaglandins and thromboxane. On the other hand extreme which a platelet plug forms at the site of injury to the blood cases of aggregation can lead to serious outcome as in septic vessel, leading to cessation of bleeding. Several aggregation shock and thrombosis (Parellada and Planas, 1977; Randall pathways have been described (Packham, 1993), one of which and Wilding, 1982; Fiedler et al., 1989; Silver et al., 1995; is the thromboxane pathway (Hamberg et al., 1974, 1975; Wolkow et al., 1997; Zaitsu et al., 1999). By comparison, Diczfalusy and Hammarstrom, 1979; Hammarstrom and Dic- NSAIDs such as aspirin reduce platelet aggregation through zfalusy, 1980). The active mediator in this pathway is throm- inhibition at the early stage of cyclooxygenase within the boxane A2, a powerful unstable pro-aggregating substance platelet but, also, in other cells/tissues, such as the blood and a vasoconstrictor of blood vessels. It is formed in plate- vessel wall, prevent the formation of all prostaglandins, some lets from arachidonic acid, a fatty acid present in mem- of which are anti-aggregatory and therefore beneficial, e.g., branes, by the enzyme, cyclooxygenase, through an interme- prostacyclin and prostaglandin E2 (Vane, 1978; Willis, 1978; Bunting et al., 1983; Harada et al., 1998). Therefore, proper This study was supported in part by a grant (MT-4181) to C.R.P.-A. from the Canadian Institutes of Health Research and from The Hospital for Sick Chil- management of thromboxane-mediated disease is desirable dren. at the level of thromboxane (synthesis and/or receptor ac- 1Associated with the Department of Pharmacology, University of Toronto, Toronto, ON M5S 1A8, Canada. tion), as this leaves the beneficial prostaglandins in place ABBREVIATIONS: NSAIDs, nonsteroidal anti-inflammatory drugs; TP receptor, thromboxane A2 receptor; ADAM, 9-anthryldiazomethane; TSI, throm- boxane synthase inhibitor; TRA, thromboxane receptor antagonist; TxB2, thromboxane B2; AA, arachidonic acid; HPLC, high-performance liquid chromatography; 12-HETE, 12(S)-hydroxyeicosa-5Z,8Z,10E,14Z-trienoic acid; HHT, 12-hydroxy-heptadeca-5Z,8E,10E-trienoic acid; PBT, hepoxilin cyclopropane analog; PBT-1, 8(S)-hydroxy-11,12-cyclopropyl-eicosa-5Z,9E,14Z-trienoic acid methyl ester; PBT-2, 8(R)-hydroxy-11,12-cyclopropyl- eicosa-5Z,9E,14Z-trienoic acid methyl ester; PBT-3, 10(S)-hydroxy-11,12-cyclopropyl-eicosa-5Z,8Z,14Z-trienoic acid methyl ester; PBT-4, 10(R)- hydroxy-11,12-cyclopropyl-eicosa-5Z,8Z,14Z-trienoic acid methyl ester; 12-LOX, 12(S)-lipoxygenase; COX, cyclooxygenase; Plase A2, phospholipase ␣ ␣ ␤ ␣ A2; PG, prostaglandin; I-BOP, [1S-[1 ,2 (Z),3 (1E,S*),4 ]]-7-[3-[3-hydroxy-4-(4-iodophenoxy)-1-butenyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-5-heptenoic acid; U46619, 9,11-dideoxy-9␣,11␣-methanoepoxy-prosta-5Z,13E-dien-1-oic acid. 618 Novel Family of Thromboxane Receptor Antagonists 619 (Bunting et al., 1983). Recently, this approach has identified Binding of 125I-BOP to Platelets. Washed platelets were pre- a new class of compounds, oxazolecarboxamide-substituted pared as described above, except that the platelet suspension was alkenoic acids with dual TSI/TRA activities (Takeuchi et al., made up at a concentration of 10 ϫ 106 cells/0.5 ml (Dorn, 1991) in a 1998). clear medium (140 mM NaCl, 5 mM KCl, 1 mM MgCl2, 1 mM CaCl2, During the course of our studies on the metabolic conver- 10 mM sodium-free HEPES, and 10 mM glucose, pH 7.3). The bind- ing assay involved the addition of radioligand (30,000 cpm 125I-BOP) sion of arachidonic acid, we discovered a novel pathway with to all tubes in triplicates, containing either various concentrations of products, hepoxilins, that showed biological actions on a va- unlabeled I-BOP (10Ϫ9-10Ϫ7 M) or PBT-3 (10Ϫ9-10Ϫ7 M) or U46619 riety of systems (Pace-Asciak et al., 1983; Pace-Asciak and (10Ϫ9-10Ϫ7 M) in 1 ␮l ethanol. Additional tubes containing excess Martin, 1984; Pace-Asciak, 1994). Since these compounds unlabeled I-BOP were included to assess the extent of nonspecific were unstable biologically, we prepared by total chemical binding. Binding was allowed to take place during 30 min at 37°C; synthesis a family of analogs, PBTs, that were both chemi- free radioligand was removed by rapid vacuum filtration through cally and biologically suitable for in vivo studies (Demin and Whatman (Maidstone, UK) GF/B glass fiber filters prewashed with Pace-Asciak, 1993). Indeed, we found that different com- clear medium. The tubes and the filters were rapidly washed with pounds within this family acted on different in vivo systems, ice-cold clear medium (three times with 3 ml). The radioactivity on e.g., insulin secretion (Pace-Asciak et al., 1999), decrease in the filters containing the ligand-receptor complexes was counted in plasma glucose (unpublished observations), or inhibition of an LKB (Uppsala, Sweden) Compugamma CS counter. Measurement of Adenyl Cyclase Activity. Human washed lung fibrosis (Pace-Asciak et al., 2000). During more compre- platelets (350 ϫ 106 cells) in 1 ml of assay buffer were preincubated hensive screening for in vitro biological actions, we discov- during 10 min at 37°C. Dimethyl sulfoxide (1 ␮l) alone (control) or ered that one of these analogs, PBT-3, potently inhibited containing various concentrations of PBT-1, -2, -3, and -4 (2.8 ϫ collagen-evoked aggregation of human platelets through se- 10Ϫ7-10Ϫ5 M final concentration) was added, and the cells were lective blockade of the thromboxane synthetic pathway (Rey- incubated for a further 5 min. The reaction was stopped by the naud et al., 2001). The present results demonstrate a far addition of 12% trichloroacetic acid, and the samples were sonicated more important and powerful action of this compound as an (four times for 3 sec). The samples were left on ice for 60 min to antagonist of the TP receptor revealing a more likely mech- extract cAMP. After centrifugation at 2500g for 15 min, the super- anism for its inhibitory actions on platelet aggregation. natants were transferred and extracted five times with 5 ml of water-saturated diethyl ether to remove the trichloroacetic acid. The aqueous phase was transferred and lyophilized. cAMP was measured 125 Experimental Procedures using specific double antibody radioimmunoassay kits with I- labeled cAMP according to the instructions by the manufacturer Materials. The hepoxilin analogs, PBT-1, -2, -3, and -4, were (Amersham Biosciences, Piscataway, NJ). Results are expressed in prepared as previously described (Demin and Pace-Asciak, 1993). picomoles/350 million cells. Experiments were performed in tripli- Collagen (Chrono-Par) was purchased from Chronolog Corp. (Hav- cate for each point and repeated twice. ertown, PA). ADAM reagent (9-anthryldiazomethane) was from Re- Measurement of COX-1 and COX-2 Activity. COX-1 and search Organics Inc. (Cleveland, OH). U46619, I-BOP, and 125I-BOP COX-2 enzyme preparations were purchased from Cayman Chemical were from Cayman Chemical (Ann Arbor, MI). (Ann Arbor, MI). Preliminary studies established that 40 U of COX-1 Isolation of Human Platelets.
Load more

Recommended publications
  • Download Product Insert (PDF)
    Product Information U-46619 Item No. 16450 CAS Registry No.: 56985-40-1 Formal Name: 9,11-dideoxy-9α,11α-methanoepoxy-prosta- 5Z,13E-dien-1-oic acid Synonym: 9,11-dideoxy-9α,11α-methanoepoxy COOH Prostaglandin F2α MF: C21H34O4 O FW: 350.5 Purity: ≥98% OH Stability: ≥2 years at -20°C Supplied as: A solution in methyl acetate Laboratory Procedures For long term storage, we suggest that U-46619 be stored as supplied at -20°C. It will be stable for at least two years. U-46619 is supplied as a solution in methyl acetate. To change the solvent, simply evaporate the methyl acetate under a gentle stream of nitrogen and immediately add the solvent of choice. Solvents such as DMSO, ethanol, and dimethyl formamide purged with an inert gas can be used. The solubility of U-46619 in these solvents is aproximately 100 mg/ml. Further dilutions of the stock solution into aqueous buffers or isotonic saline should be made prior to performing biological experiments. Ensure that the residual amount of organic solvent is insignificant since organic solvents may have physiological effects at low concentrations. If an organic solvent-free solution of U-46619 is needed, it can be prepared by evaporating the methyl acetate and directly dissolving the neat oil in aqueous buffers. The solubility of U-46619 in PBS (pH 7.2) is approximately 2 mg/ml. We do not recommend storing the aqueous solution for more than one day. 1 U-46619 is a stable analog of the endoperoxide prostaglandin H2, and a TP receptor agonist.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 7.803,838 B2 Davis Et Al
    USOO7803838B2 (12) United States Patent (10) Patent No.: US 7.803,838 B2 Davis et al. (45) Date of Patent: Sep. 28, 2010 (54) COMPOSITIONS COMPRISING NEBIVOLOL 2002fO169134 A1 11/2002 Davis 2002/0177586 A1 11/2002 Egan et al. (75) Inventors: Eric Davis, Morgantown, WV (US); 2002/0183305 A1 12/2002 Davis et al. John O'Donnell, Morgantown, WV 2002/0183317 A1 12/2002 Wagle et al. (US); Peter Bottini, Morgantown, WV 2002/0183365 A1 12/2002 Wagle et al. (US) 2002/0192203 A1 12, 2002 Cho 2003, OOO4194 A1 1, 2003 Gall (73) Assignee: Forest Laboratories Holdings Limited 2003, OO13699 A1 1/2003 Davis et al. (BM) 2003/0027820 A1 2, 2003 Gall (*) Notice: Subject to any disclaimer, the term of this 2003.0053981 A1 3/2003 Davis et al. patent is extended or adjusted under 35 2003, OO60489 A1 3/2003 Buckingham U.S.C. 154(b) by 455 days. 2003, OO69221 A1 4/2003 Kosoglou et al. 2003/0078190 A1* 4/2003 Weinberg ...................... 514f1 (21) Appl. No.: 11/141,235 2003/0078517 A1 4/2003 Kensey 2003/01 19428 A1 6/2003 Davis et al. (22) Filed: May 31, 2005 2003/01 19757 A1 6/2003 Davis 2003/01 19796 A1 6/2003 Strony (65) Prior Publication Data 2003.01.19808 A1 6/2003 LeBeaut et al. US 2005/027281.0 A1 Dec. 8, 2005 2003.01.19809 A1 6/2003 Davis 2003,0162824 A1 8, 2003 Krul Related U.S. Application Data 2003/0175344 A1 9, 2003 Waldet al. (60) Provisional application No. 60/577,423, filed on Jun.
    [Show full text]
  • Role of Proaggregatory and Antiaggregatory Prostaglandins in Hemostasis
    Role of proaggregatory and antiaggregatory prostaglandins in hemostasis. Studies with combined thromboxane synthase inhibition and thromboxane receptor antagonism. P Gresele, … , G Pieters, J Vermylen J Clin Invest. 1987;80(5):1435-1445. https://doi.org/10.1172/JCI113223. Research Article Thromboxane synthase inhibition can lead to two opposing effects: accumulation of proaggregatory cyclic endoperoxides and increased formation of antiaggregatory PGI2 and PGD2. The elimination of the effects of the cyclic endoperoxides by an endoperoxide-thromboxane A2 receptor antagonist should enhance the inhibition of hemostasis by thromboxane synthase blockers. We have carried out a series of double-blind, placebo-controlled, crossover studies in healthy volunteers to check if this hypothesis may be operative in vivo in man. In a first study, in 10 healthy male volunteers, the combined administration of the thromboxane receptor antagonist BM 13.177 and the thromboxane synthase inhibitor dazoxiben gave stronger inhibition of platelet aggregation and prolonged the bleeding time more than either drug alone. In a second study, in 10 different healthy male volunteers, complete inhibition of cyclooxygenase with indomethacin reduced the prolongation of the bleeding time by the combination BM 13.177 plus dazoxiben. In a third study, in five volunteers, selective cumulative inhibition of platelet TXA2 synthesis by low-dose aspirin inhibited platelet aggregation and prolonged the bleeding time less than the combination BM 13.177 plus dazoxiben. In vitro, in
    [Show full text]
  • Vasoactive Responses of U46619, PGF2 , Latanoprost, and Travoprost
    Vasoactive Responses of U46619, PGF2␣, Latanoprost, and Travoprost in Isolated Porcine Ciliary Arteries Ineta Vysniauskiene, Reto Allemann, Josef Flammer, and Ivan O. Haefliger PURPOSE. To compare the vasoactive properties of the prosta- these responses can be modulated by SQ 29548 (TP-receptor noids U46619 (thromboxane A2 analogue), prostaglandin F2␣ antagonist) or AL-8810 (FP-receptor antagonist). (PGF2␣), latanoprost free acid, and travoprost free acid in isolated porcine ciliary arteries. METHODS. In a myograph system (isometric force measure- MATERIAL AND METHODS ment), quiescent vessels were exposed (cumulatively) to U46619, PGF , latanoprost, or travoprost (0.1 nM–0.1 mM). 2␣ Vessels Preparation Experiments were also conducted in the presence of SQ 29548 (TP-receptor antagonist; 3–10 ␮M) or AL-8810 (FP-receptor Porcine eyes were obtained from an abattoir immediately after death. antagonist; 3–30 ␮M). Contractions were expressed as the In cold modified Krebs-Ringer solution (NaCl 118 mM, KCl 4.7 mM, percentage of 100 mM potassium chloride-induced contrac- CaCl2 2.5 mM, K2PO4 1.2 mM, MgSO4 1.2 mM, NaHCO3 25 mM, tions. glucose 11.1 mM, and EDTA 0.026 mM), ciliary arteries were dissected 5 ␮ RESULTS. In quiescent vessels, contractions (concentration–re- and cut into 2-mm segments. In an organ chamber, two 45- m Ϯ tungsten wires were passed through the vessel’s lumen and attached to sponse curves) induced by (0.1 mM) PGF2␣ (87.9% 3.5%), U46619 (66.7% Ϯ 4.1%), and latanoprost (62.9% Ϯ 3.6%) were a force transducer for isometric force measurements (Myo-Interface; JP more pronounced (P Յ 0.001) than those induced by tra- Trading, Aarhus, Denmark).
    [Show full text]
  • Effect of Prostanoids on Human Platelet Function: an Overview
    International Journal of Molecular Sciences Review Effect of Prostanoids on Human Platelet Function: An Overview Steffen Braune, Jan-Heiner Küpper and Friedrich Jung * Institute of Biotechnology, Molecular Cell Biology, Brandenburg University of Technology, 01968 Senftenberg, Germany; steff[email protected] (S.B.); [email protected] (J.-H.K.) * Correspondence: [email protected] Received: 23 October 2020; Accepted: 23 November 2020; Published: 27 November 2020 Abstract: Prostanoids are bioactive lipid mediators and take part in many physiological and pathophysiological processes in practically every organ, tissue and cell, including the vascular, renal, gastrointestinal and reproductive systems. In this review, we focus on their influence on platelets, which are key elements in thrombosis and hemostasis. The function of platelets is influenced by mediators in the blood and the vascular wall. Activated platelets aggregate and release bioactive substances, thereby activating further neighbored platelets, which finally can lead to the formation of thrombi. Prostanoids regulate the function of blood platelets by both activating or inhibiting and so are involved in hemostasis. Each prostanoid has a unique activity profile and, thus, a specific profile of action. This article reviews the effects of the following prostanoids: prostaglandin-D2 (PGD2), prostaglandin-E1, -E2 and E3 (PGE1, PGE2, PGE3), prostaglandin F2α (PGF2α), prostacyclin (PGI2) and thromboxane-A2 (TXA2) on platelet activation and aggregation via their respective receptors. Keywords: prostacyclin; thromboxane; prostaglandin; platelets 1. Introduction Hemostasis is a complex process that requires the interplay of multiple physiological pathways. Cellular and molecular mechanisms interact to stop bleedings of injured blood vessels or to seal denuded sub-endothelium with localized clot formation (Figure1).
    [Show full text]
  • Activation of the Murine EP3 Receptor for PGE2 Inhibits Camp Production and Promotes Platelet Aggregation
    Activation of the murine EP3 receptor for PGE2 inhibits cAMP production and promotes platelet aggregation Jean-Etienne Fabre, … , Thomas M. Coffman, Beverly H. Koller J Clin Invest. 2001;107(5):603-610. https://doi.org/10.1172/JCI10881. Article The importance of arachidonic acid metabolites (termed eicosanoids), particularly those derived from the COX-1 and COX-2 pathways (termed prostanoids), in platelet homeostasis has long been recognized. Thromboxane is a potent agonist, whereas prostacyclin is an inhibitor of platelet aggregation. In contrast, the effect of prostaglandin E2 (PGE2) on platelet aggregation varies significantly depending on its concentration. Low concentrations of PGE2 enhance platelet aggregation, whereas high PGE2 levels inhibit aggregation. The mechanism for this dual action of PGE2 is not clear. This study shows that among the four PGE2 receptors (EP1–EP4), activation of EP3 is sufficient to mediate the proaggregatory actions of low PGE2 concentration. In contrast, the prostacyclin receptor (IP) mediates the inhibitory effect of higher PGE2 concentrations. Furthermore, the relative activation of these two receptors, EP3 and IP, regulates the intracellular level of cAMP and in this way conditions the response of the platelet to aggregating agents. Consistent with these findings, loss of the EP3 receptor in a model of venous inflammation protects against formation of intravascular clots. Our results suggest that local production of PGE2 during an inflammatory process can modulate ensuing platelet responses. Find the latest version: https://jci.me/10881/pdf Activation of the murine EP3 receptor for PGE2 inhibits cAMP production and promotes platelet aggregation Jean-Etienne Fabre,1 MyTrang Nguyen,1 Krairek Athirakul,2 Kenneth Coggins,1 John D.
    [Show full text]
  • Acute Necrotizing Pancreatitis in Rats
    ACUTE NECROTIZING PANCREATITIS IN RATS Acute necrotizerende pancreatitis in ratten PROEFSCHRIFT TER VERKRIJGING VAN DE GRAAD VAN DOCTOR IN DE GENEESKUNDE AAN DE ERASMUS UNIVERSITEIT ROTTERDAM OP GEZAG VAN DE RECTOR MAGNIFICUS PROF. DR. A.H.G. RINNOOY KAN EN VOLGENS BESLUIT VAN HET COLLEGE VAN DEKANEN. DE OPENBARE VERDEDIGING ZAL PLAATSVINDEN OP VRIJDAG 22 JANUARI 1988 TE 15.45 UUR door BAAN VAN OOIJEN geboren te Rotterdam Druk: Krips Repro Meppel 1987 PROMOTIECOMMISSIE PROMOTOREN PROF. J.H.P. WILSON PROF. DR. J. JEEKEL OVERIGE LEDEN: PROF. DR. I.L. BONTA PROF. DR. J.L. TERPSTRA 1987 B. van Ooijen No part of this book may be reproduced in any form, by print, photoprint, microfilm or any other means without written permission from the publisher. De druk van dit proefschrift werd mede mogelijk gemaakt door financiele steun van het Bronovo Researchfonds. Wat heb ik dat ik niet gekregen heb? aJNTENTS page ABBREVIATIONS CHAPTER 1: INTRODUCTION AND AIM OF THE STUDY. 1 1.1. References 3 CHAPTH• 2: ETIOLOGICAL FACTORS IN ACUTE PANCREATITIS. 2. 1. Introduction 4 2.2. Etiological factors 5 2.2.1. Mechanical block at ampulla 6 a. Biliary tract disease 6 a-1. Bile reflux 7 a-2. Pancreatic duct obstruction 8 b. Obstruction at the level of the ampulla 8 b-1. Pancreas divisum 9 c. Duodenal disorders 9 2.2.2. Vascular factors and ischemia 9 2.2.3. Toxic and metabolic factors 10 a. Alcoholism 10 b. Hypercalcemia 11 c. Hypertriglyceridemia 12 d. Other metabolic causes 12 e. Drugs 12 2.2.4. Infection 13 2.2.5.
    [Show full text]
  • Prostaglandins and Other Lipid Mediators
    Prostaglandins & other Lipid Mediators 122 (2016) 18–27 Contents lists available at ScienceDirect Prostaglandins and Other Lipid Mediators Original research article In silico modelling of prostacyclin and other lipid mediators to nuclear receptors reveal novel thyroid hormone receptor antagonist properties ∗ Noelia Perez Diaz, Mire Zloh, Pryank Patel, Louise S. Mackenzie Life and Medical Sciences, University of Hertfordshire, Hatfield AL10 9AB, UK a r t i c l e i n f o a b s t r a c t Article history: Prostacyclin (PGI2) is a key mediator involved in cardiovascular homeostasis, acting predominantly on Received 10 August 2015 two receptor types; cell surface IP receptor and cytosolic peroxisome proliferator activated receptor Received in revised form (PPAR) ␤/␦. Having a very short half-life, direct methods to determine its long term effects on cells 19 November 2015 is difficult, and little is known of its interactions with nuclear receptors. Here we used computational Accepted 7 December 2015 chemistry methods to investigate the potential for PGI2, beraprost (IP receptor agonist), and GW0742 Available online 11 December 2015 ␤ ␦ (PPAR / agonist), to bind to nuclear receptors, confirmed with pharmacological methods. In silico screening predicted that PGI , beraprost, and GW0742 have the potential to bind to different Abbreviations: 2 nuclear receptors, in particular thyroid hormone ␤ receptor (TR␤) and thyroid hormone ␣ receptor (TR␣). MLS, MLS000389544 Docking analysis predicts a binding profile to residues thought to have allosteric control on the TR ligand NSAID, non-steroidal anti-inflammatory drug binding site. Luciferase reporter assays confirmed that beraprost and GW0742 display TR␤ and TR␣ −5 −6 × × PPAR␤/␦, peroxisome proliferator activated antagonistic properties; beraprost IC50 6.3 10 mol/L and GW0742 IC50 4.9 10 mol/L.
    [Show full text]
  • Role of Curcumin on Tumor Angiogenesis in Hepatocellular Carcinoma
    Naresuan University Journal 2008; 16(3): 239-254 239 Role of Curcumin on Tumor Angiogenesis in Hepatocellular Carcinoma Pornphrom Chintana Department of Physiology, Faculty of Medical Science, Naresuan University, Phitsanulok 65000, Thailand. Corresponding author. E-mail address: [email protected] (P. Chintana) Received 14 July 2008; accepted 24 December 2008 Summary Hepatocellular carcinoma (HCC) is a malignant tumor characterized by active neovascularization. Vascular endothelial growth factor (VEGF) is the most important angiogenic factor that regulates the HCC development. Overexpression of VEGF enhances the HCC tumor growth associated with increase of angiogenesis in the tumor, whereas suppression of VEGF attenuates the tumor growth. Similarly, the cyclooxygenase-2 (COX-2) expression stepwisely increases during hepatocarcinogenesis. Curcurmin has been shown to inhibit several angiogenic biomarkers including, VEGF and COX-2 expression. Therefore, curcumin could be used as a candidate for the combined drug treatment for HCC in the future. Keywords: Curcumin; Angiogenesis; Hepatocellular carcinoma; VEGF; COX-2 INTRODUCTION greater practical significance than non-selective cytotoxic therapies to control the tumor growth Hepatocellular carcinoma (HCC) is one of the and metastasis by targeting angiogenesis. Since, five most common cancers worldwide, with a many dietary and non-dietary phytochemicals do particularly high prevalence in Asian countries due not affect survival of normal cells and also possess to endemic hepatitis B virus infection (Parkin et al., anti-angiogenic as well as anti-tumorigenic 2001). In Thailand, it is the most common cause of activities, it could be a rationale approach to examine death in men (Vatanasapt et al., 2002). Surgery, their inhibitory effect on tumor angiogenesis.
    [Show full text]
  • G Protein-Coupled Receptors
    S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2015/16: G protein-coupled receptors. British Journal of Pharmacology (2015) 172, 5744–5869 THE CONCISE GUIDE TO PHARMACOLOGY 2015/16: G protein-coupled receptors Stephen PH Alexander1, Anthony P Davenport2, Eamonn Kelly3, Neil Marrion3, John A Peters4, Helen E Benson5, Elena Faccenda5, Adam J Pawson5, Joanna L Sharman5, Christopher Southan5, Jamie A Davies5 and CGTP Collaborators 1School of Biomedical Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK, 2Clinical Pharmacology Unit, University of Cambridge, Cambridge, CB2 0QQ, UK, 3School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, UK, 4Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK, 5Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/ 10.1111/bph.13348/full. G protein-coupled receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading.
    [Show full text]
  • Pharmaceutical Appendix to the Tariff Schedule 2
    Harmonized Tariff Schedule of the United States (2006) – Supplement 1 (Rev. 1) Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2006) – Supplement 1 (Rev. 1) Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 2 Table 1. This table enumerates products described by International Non-proprietary Names (INN) which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service (CAS) registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known. Product CAS No. Product CAS No. ABACAVIR 136470-78-5 ACEXAMIC ACID 57-08-9 ABAFUNGIN 129639-79-8 ACICLOVIR 59277-89-3 ABAMECTIN 65195-55-3 ACIFRAN 72420-38-3 ABANOQUIL 90402-40-7 ACIPIMOX 51037-30-0 ABARELIX 183552-38-7 ACITAZANOLAST 114607-46-4 ABCIXIMAB 143653-53-6 ACITEMATE 101197-99-3 ABECARNIL 111841-85-1 ACITRETIN 55079-83-9 ABIRATERONE 154229-19-3 ACIVICIN 42228-92-2 ABITESARTAN 137882-98-5 ACLANTATE 39633-62-0 ABLUKAST 96566-25-5 ACLARUBICIN 57576-44-0 ABUNIDAZOLE 91017-58-2 ACLATONIUM NAPADISILATE 55077-30-0 ACADESINE 2627-69-2 ACODAZOLE 79152-85-5 ACAMPROSATE 77337-76-9 ACONIAZIDE 13410-86-1 ACAPRAZINE 55485-20-6 ACOXATRINE 748-44-7 ACARBOSE 56180-94-0 ACREOZAST 123548-56-1 ACEBROCHOL 514-50-1 ACRIDOREX 47487-22-9 ACEBURIC
    [Show full text]
  • Pharmaceutical Appendix to the Tariff Schedule 2
    Harmonized Tariff Schedule of the United States (2007) (Rev. 2) Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2007) (Rev. 2) Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 2 Table 1. This table enumerates products described by International Non-proprietary Names (INN) which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service (CAS) registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known. ABACAVIR 136470-78-5 ACIDUM LIDADRONICUM 63132-38-7 ABAFUNGIN 129639-79-8 ACIDUM SALCAPROZICUM 183990-46-7 ABAMECTIN 65195-55-3 ACIDUM SALCLOBUZICUM 387825-03-8 ABANOQUIL 90402-40-7 ACIFRAN 72420-38-3 ABAPERIDONUM 183849-43-6 ACIPIMOX 51037-30-0 ABARELIX 183552-38-7 ACITAZANOLAST 114607-46-4 ABATACEPTUM 332348-12-6 ACITEMATE 101197-99-3 ABCIXIMAB 143653-53-6 ACITRETIN 55079-83-9 ABECARNIL 111841-85-1 ACIVICIN 42228-92-2 ABETIMUSUM 167362-48-3 ACLANTATE 39633-62-0 ABIRATERONE 154229-19-3 ACLARUBICIN 57576-44-0 ABITESARTAN 137882-98-5 ACLATONIUM NAPADISILATE 55077-30-0 ABLUKAST 96566-25-5 ACODAZOLE 79152-85-5 ABRINEURINUM 178535-93-8 ACOLBIFENUM 182167-02-8 ABUNIDAZOLE 91017-58-2 ACONIAZIDE 13410-86-1 ACADESINE 2627-69-2 ACOTIAMIDUM 185106-16-5 ACAMPROSATE 77337-76-9
    [Show full text]