![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
NEUROPHARMACOLOGY
Discovery Biology Research (A.M., H.O., T.O., K.T., Y.M., J.T.), Pharmacokinetics, Dynamics, and Metabolism (M.M.), and Discovery Chemistry Research (K.N., T.K., Y.O.), Pfizer Global Research and Development, Aichi, Japan
Received February 28, 2007; accepted May 9, 2007.
 |
Abstract |
|---|
 Top Abstract Materials and MethodsResultsDiscussionReferences |
|---|
; Hinz and Brune, 2002), but prolonged use of COX-2-selective inhibitors may, as with NSAIDs, confer a risk of cardiovascular events, including hypertension, edema, heart attack, and stroke (Graham et al., 2005; Lenzer, 2005; Solomon et al., 2005). The cause of the adverse cardiovascular effects remains unclear, but it may include an imbalance in prostacyclin and thromboxane levels in the endothelium (McAdam et al., 1999; Bing and Lomnicka, 2002; Cheng et al., 2002) and blockade of prostanoid actions on renal function (Nasrallah and Hebert, 2005). Identification of new therapeutic targets downstream of COX may provide an opportunity for the development of new analgesics that interfere with prostanoid proinflammatory and pronociceptive actions with less gastrointestinal, renal, and cardiovascular risk.
One PG downstream from the cyclooxygenase enzyme, PGE2, has long been recognized as a pivotal mediator of pain and inflammation (Dannhardt and Kiefer, 2001). The pathological and homeostatic effects of PGE2 are mediated via a family of G protein-coupled receptor subtypes, designated EP1–4. These receptor subtypes are distinguished by their distinct pattern of tissue distribution, signaling pathways, and physiological functions (Coleman et al., 1994b). EP1 is coupled to intracellular Ca2+ mobilization, EP2 and EP4 are coupled to stimulation of adenylate cyclase via Gs protein, and EP3 is coupled to inhibition of adenylate cyclase via Gi protein. Studies performed either in mutant mice lacking the individual PG receptors (Murata et al., 1997; Minami et al., 2001; Stock et al., 2001) or with synthetic EP receptor agonist/antagonist (Minami et al., 1994; Nakayama et al., 2002) have not yet provided a coherent picture of which EP receptors are responsible for inflammatory pain. Recently it has been reported that EP4 knockdown with intrathecally delivered short hairpin RNA attenuates inflammation-induced thermal and mechanical behavioral hypersensitivity (Lin et al., 2006), suggesting that EP4 is a potential target for the pharmacological treatment of inflammatory pain. However, developing subtype-selective EP receptor antagonists has been difficult because of the existence of multiple PG receptor subtypes and the lack of the selectivity of synthetic PG analogs. Thus, defining the contribution of EP receptor subtype to pain sensitization on the basis of available antagonists remains elusive.
Here, we report the in vitro and in vivo characterization of a novel, potent, and selective EP4 antagonist, CJ-023,423 (Fig. 1). CJ-023,423 competitively inhibits PGE2 binding and PGE2-evoked elevation in intracellular cAMP at both human and rat EP4 receptors. Oral administration of CJ-023,423 dose-dependently reduced hyperalgesia in animal models of inflammatory pain, and it produced comparable efficacy to NSAIDs, which block PG synthesis of all of the COX products. These data suggest that the EP4 receptor plays a dominant role in mediating the pronociceptive action of PGE2. It is downstream of COX, and particularly, the identification of it as a single PG receptor subtype responsible for pain provides the basis for novel therapeutic approaches for better tolerated analgesics.
|
|
Materials and Methods |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Stable Expression of Prostanoid Receptors in the Human Embryonic Kidney 293 Cell Line. Prostanoid receptor cDNA clones were obtained by reverse transcription and polymerase chain reaction. The amplified DNA fragment was isolated by electrophoresis on a 1.2% agarose gel, digested with restricted enzymes, and subcloned into the appropriate site of the mammalian expression vector pcDNA3 (Invitrogen, Carlsbad, CA). To generate stable transfectants, plasmid DNA was transfected into HEK293 cells (American Type Culture Collection, Manassas, VA) using Lipofectamine (Invitrogen) according to the manufacturer's instructions. HEK cells expressing the cDNA together with the G-418 (Geneticin; Invitrogen) resistance gene were selected in Dulbecco's modified Eagle's medium (DMEM) (Invitrogen) supplemented with 10% heat-inactivated fetal bovine serum (FBS). Individual colonies were isolated after 2 weeks of growth under selection using the cloning ring method, and they were subsequently expanded into clonal cell lines. Expression of the receptors was assessed by receptor binding assays.
Prostanoid Receptor Radioligand Binding Assays. A competitive binding assay was performed in a final incubation volume of 1 ml in 10 mM MES/KOH buffer, pH 6, containing 10 mM MgCl2 and 1 mM EDTA for EP1, EP2, EP3, and FP or in 50 mM Tris-HCl buffer, pH 7.4, containing 10 mM MgCl2 and 1 mM EDTA for DP and IP or in DMEM buffer containing 0.1% NaN3, pH 7.4, for EP4. Saturation studies were conducted with [3H]PGE2 (GE Healthcare, Little Chalfont, Buckinghamshire, UK) for EP1–4, [3H]PGD2 (GE Healthcare) for DP, [3H]PGF2
(GE Healthcare) for FP, and [3H]iloprost (GE Healthcare) for IP in concentrations ranging from 0.015 to 32 nM. Membranes were prepared from stably transfected HEK293 cells expressing EP subtypes as well as those for PGD2, PGF2, and prostacyclin. Assays were initiated by the addition of membrane proteins (EP1, 40 µg; EP2, 40 µg; EP3, 5 µg; EP4, 100 µg; DP, 30 µg; FP, 60 µg; and IP, 100 µg) into the incubation mixture. After 60-min incubation at room temperature, the reaction was terminated by rapid vacuum filtration over glass fiber filer papers presoaked in 0.2% polyethyleneimine (Brandel Inc., Gaithersburg, MD) using a Brandel cell harvester followed by two washes with assay buffer. Receptor-bound radioactivity was quantified by liquid scintillation counter, and nonspecific binding was determined in the presence of unlabeled 10 µM of the corresponding nonradioactive prostanoid. IC50 values of CJ-023,423 from competitive binding assay were determined using 1 nM ligand concentration, [L]. To obtain Ki values of CJ-023,423, these parameters were applied to the Cheng and Prusoff (1973) equation Ki = IC50/(1 + [L]/Kd). Displacement binding at the TP receptor prepared from human platelet membranes was performed at Cerep (Celle L'Evescault, France).
Isolation and Culture of Rat Dorsal Root Ganglion Cells. Primary cultures of dissociated neonatal DRG neurons were prepared according to the method described previously (Garland et al., 1995). In brief, Sprague-Dawley (SD) rats (1–4 days) were anesthetized, and the spinal cords were surgically removed and placed into ice-cold sterile Hanks' medium (Invitrogen). DRG were digested by the serial addition of 0.1% collagenase (Sigma-Aldrich, St. Louis, MO) and 0.125% trypsin (Invitrogen) for 30 min each at 37°C. After digestion, DRG were carefully dissociated by mechanical agitation and then centrifuged. The cell pellet was resuspended in minimal essential medium (Invitrogen) supplemented with 10% FBS, 5 g/l glucose (Sigma-Aldrich), 40 mg/l gentamicin (Invitrogen), 100 U/ml penicillin (Invitrogen), 100 µg/ml streptomycin (Invitrogen), 100 ng/ml nerve growth factor (Sigma-Aldrich), and 10 µM cytokine arabinoside (Sigma-Aldrich). Cells were plated onto poly-D-lysine and laminin-precoated 96-well culture plates (BD Biosciences, San Jose, CA) at 1.5 x 104 cells/well. DRG cells were maintained at 37°C ina5%CO2 for 4 days, and arabinoside was removed before assays.
Cyclic AMP Assays. HEK293 cells were maintained in DMEM containing 10% FBS and 600 µg/ml G-418. The cells were harvested by incubation with phosphate-buffered saline, and then they were suspended in DMEM at 60 x 104 cells/ml.
The reaction was started in duplicate by addition of cells (3 x 104 cells/well) into the incubation mixture containing IBMX (PDE inhibitor, final concentration 200 nM) and appropriate concentrations of PGE2 and CJ-023,423. The reaction mixture was incubated at 37°C for 10 min, and then it was heated at 98°C for 5 min to terminate reaction using thermal cycler. Once they had returned to room temperature, samples were sonicated for 10 min. Measurement of cAMP content was performed by scintillation proximity assay system (RPA556; GE Healthcare). The concentration-response curves for PGE2 were fitted by nonlinear regression (sigmoid Emax model) using Prism (GraphPad Software Inc., San Diego, CA), and Schild plots were made with EC50 values to examine the nature of the antagonist interaction with the receptor by the Schild regression as follows: antagonist-induced parallel shifts of concentration-response curves to PGE2 were calculated as the ration (concentration ratio; CR) of equieffective concentrations of agonist (EC50) obtained in the presence and in the absence of antagonist. Estimates of log[CR – 1] were plotted against log[antagonist concentration]. The slopes of liner regression lines were calculated to ascertain the competitive antagonist behavior. The antagonist potency was expressed in terms of pA2 calculated from the equation pA2 = log[CR – 1] – log[antagonist concentration] from each experiment.
Animals. All procedures were carried out with the approval of the Animal Ethics Committee at Pfizer's Nagoya Laboratories (Aichi, Japan) according to the Laboratory Animal Welfare guidelines. Male SD rats (115–250 g) were purchased from Charles River Laboratories Japan Inc. (Kanagawa, Japan). Animals were housed in pairs with free access to food and water. The animals were kept under conditions of constant temperature (23 ± 2°C) and humidity (55 ± 15%) with a 12-h light/dark cycle (lights on 7:00 AM). Before the start of the experiment, the animals were housed under these conditions for 4 to 5 days. The rats were fasted overnight before experimental use, and each drug was orally administered suspended with 0.1% methylcellulose (MC; Wako Pure Chemicals., Osaka, Japan) in a volume of 10 ml/kg.
PGE2-Induced Thermal Hyperalgesia. Hyperalgesia was induced by intraplantar injection of 100 ng of PGE2 (Sigma-Aldrich) in 5% dimethyl sulfoxide/saline (100 µl). CJ-023,423 suspended in 0.1% MC was administered orally 30 min before PGE2 injection. Rats were placed in plastic cages of plantar test apparatus (Ugo Basile, Comerio, Italy), and the mobile radiant heat source was focused on the right hind paws of the rats. Latency (seconds) to the thermal stimulation was measured both before and after PGE2 injection. The change in thermal nociceptive threshold was calculated as follows: percentage of change in pain threshold = 100 x [(latency after PGE2 injection) – (latency before PGE2 injection)]/(latency before PGE2 injection).
Carrageenan-Induced Mechanical Hyperalgesia. Hyperalgesia was induced by intraplantar injection of 0.1 ml of 1% (w/v) 
-carrageenan (Picnin A; Zushikagaku Laboratory, Tokyo, Japan). The test compounds suspended in 0.1% MC were administered orally at 5.5 h after the carrageenan injection. The pain threshold was measured using an analgesy meter (Ugo Basile) at 4, 5, 6.5, 7.5, and 8 h after the carrageenan injection, and the change of pain threshold was calculated.
Complete Freund's Adjuvant-Induced Weight-Bearing Deficit. In male 7-week-old SD rats (Charles River Laboratories Japan Inc.), 300 µgof Mycobacterium tuberculosis H37 RA (Difco, Detroit, MI) in 100 µl of liquid paraffin (Wako Pure Chemicals) (CFA) was injected into the right hind footpad. Two days after CFA injection, changes in hind paw weight distribution between the right (inflamed) and the left (contralateral) limbs were measured as an index of pain using a Linton Incapacitance tester (Linton Instrumentation, Norfolk, UK). Each animal was placed in the apparatus, and the weight load exerted by the hind paws was measured. The duration of the measurement was adjusted to 5 s. Rats with a weight load difference of 40 to 100 g on each paw were selected. Test compounds suspended in 0.1% MC were administered orally, and their analgesic effects were examined (0.5, 1, 2, 4, and 6 h after drug administration). Rats were kept fed during the experiment.
Statistics. Statistical analyses of the data were performed using the StatView (Abacus Concepts, Berkeley, CA) statistical package. Differences between treatment groups were tested by one-way ANOVA and unpaired two-tailed Student's t test. P values less than 0.05 at 95% confidence level were considered significant. All values in the text and figures are mean ± S.E.M.
|
|
Results |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
|
CJ-023,423 Inhibits PGE2-Evoked Intracellular cAMP Elevation in HEK293 Cells Expressing EP4 Receptors. PGE2 dose-dependently increased intracellular cAMP accumulation at human EP4 receptors expressed in HEK293 cells. Increasing concentrations of CJ-023,423 produced a rightward shift in the concentration-response curve for PGE2 without modulating the maximal cAMP production (Fig. 3A). The pA2 value was calculated as 8.3 ± 0.03 with a slope of 1.3 ± 0.1 (n = 3) by Schild plot analysis (Arunlakshana and Schild, 1959). These experiments were repeated using HEK293 cells transfected with cDNA encoding the rat EP4 receptor, resulting in a pA2 value of 8.2 ± 0.2 with a slope of 1.2 ± 0.1 (n = 4) (Fig. 3B). CJ-023,423 did not show any agonist activity at the human and rat recombinant EP4 receptors (data not shown). These data suggest that CJ-023,423 is a competitive antagonist at the human and rat EP4 receptors.
|
). We have attempted to determine the contribution of the EP4 receptor subtype in modulating adenylyl cyclase activity in isolated DRG neurons. CJ-023,423 inhibited PGE2-evoked intracellular cAMP elevation in rat DRG cells with an IC50 of 41 ± 15 nM (n = 3) (Fig. 4). These data suggest that PGE2-mediated signal transduction is mediated by EP4 receptors in the rat DRG cells.
|
|
|
CJ-023,423 Reverses Carrageenan-Induced Mechanical Hyperalgesia in Rats. Carrageenan injection into the rat footpad resulted in the induction of hyperalgesia to peripheral mechanical stimuli, peaking 4 to 8 h after treatment. Paw withdrawal thresholds (PWT) were recorded before and after intraplantar injection of carrageenan. Untreated rats displayed a PWT of approximately 120 g. Carrageenan-treated rats reached maximum sensitivity 5 h after injection with a PWT of approximately 50 to 60 g. Test compounds were administered 5.5 h after carrageenan injection, and PWT was recorded in the carrageenan-treated paw 1, 2, and 2.5 h after dosing. CJ-023,423 (3, 10, 30, and 100 mg/kg p.o.) dose-dependently increased PWT (reduced hyperalgesia) on the carrageenan-treated paw with the maximal effect of 64% reversal at 100 mg/kg. (Fig. 7). These results indicate that CJ-023,423, when administered therapeutically, reduces carrageenan-induced mechanical hyperalgesia. Its therapeutic effect (100 mg/kg p.o.) was comparable with that observed with the dual COX-1/COX-2 inhibitor piroxicam (10 mg/kg p.o.) in terms of efficacy.
|
|
|
Discussion |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
PGE2 has long been recognized as a key mediator of peripheral inflammatory pain. Treatment with a monoclonal anti-PGE2 antibody reverses carrageenan-induced hyperalgesia to the same extent as NSAIDs, indicating that PGE2 specifically plays a key role in inflammatory pain (Zhang et al., 1997). However, it has been challenging to get a clear understanding on the specific contribution each of the different EP receptor subtypes has on inflammatory pain. A genetic approach relying primarily on studying knockout mice has not yet provided conclusive evidence, and in some cases, contradictory findings regarding which EP subtype mediates the pronociceptive effects of PGE2. For example, abdominal writhing in response to an intraperitoneal proinflammatory irritant is significantly attenuated in knockout mice for IP and EP3 but not for the EP1, EP2, or EP4 receptors (Ueno et al., 2001); however, another study found the importance of EP1 in nociception using a similar model (Stock et al., 2001). The relevance of this acute visceral irritant model to somatic inflammatory pain is uncertain. More controversial is the contribution of the different EP receptor subtypes to spinal PGE2-evoked pain response. Whereas intrathecal PGE2 induces allodynia in EP3-knockout mice, but not in EP1-knockout mice, low doses of PGE2-induced hyperalgesia are meditated by the EP3 subtype (Minami et al., 2001). EP2-knockout mice also show a lack of intrathecal PGE2-evoked hyperalgesia (Reinold et al., 2005).
Few antagonists for the EP receptors are available; however, some selective EP1 receptor antagonists exist and the EP1 receptor subtype has been considered as a potential target for analgesia. Peripheral administration of the EP1-selective antagonist ONO-8711 effectively inhibits the mechanical hyperalgesia induced by incision (Omote et al., 2001). Moreover, intrathecal ONO-8711 inhibits the hyperalgesia induced by carrageenan (Nakayama et al., 2002). To date, at least one EP1 receptor antagonist, ZD-6416, has entered clinical evaluation for visceral pain (Sarkar et al., 2003), but its clinical development has been discontinued. The antagonists for EP4 receptors used for pharmacological inactivation of EP4 subtype are not selective, and many of these compounds act at multiple prostanoid receptor subtypes. For example, the commonly used EP4 antagonist AH23848 (Coleman et al., 1994a; Boie et al., 1997) has a very weak affinity to EP4 receptors with a Ki value of 8010 nM, and it actually has the highest affinity for TP receptors. EP4A (Machwate et al., 2001) and the recently discovered GW6273678X (Wilson et al., 2006) are claimed to be potent and selective competitive antagonists of human EP4 receptors. However, EP4A possesses significant TP and EP3 receptor binding affinity, and GW6273678X, one of the most potent and selective human EP4 receptor antagonists reported so far, also has equal binding affinities for human EP4 and TP receptors. CJ-023,423 is a highly potent human and rat EP4 subtype antagonist, although it has very weak affinity to the human DP receptor subtype (Ki = 2926 nM). Affinities for all other human prostanoid receptors are not substantial (Ki =>5000 nM). To our knowledge, CJ-023,423 is the most selective human EP4 receptor antagonist.
In an in vivo model of acute pain, PGE2-induced thermal hyperalgesia, CJ-023,423 demonstrates that the EP4 receptor has a predominant role in mediating PGE2-evoked nociceptive responses. This peripheral PGE2-induced thermal hyperalgesia is reduced in EP1-deficient mice, although its effect is not very robust (Moriyama et al., 2005). In the absence of receptor-specific antagonists, the cellular mechanisms that mediate the PGE2-evoked hyperalgesia are still unclear. In mouse DRG neurons, PGE2 increases transient receptor potential vanilloid 1 activity via EP1 and EP4 receptors through protein kinase C- and protein kinase A-dependent pathways, respectively (Moriyama et al., 2005). Rat DRG culture studies with antisense oligonucleotides for prostanoid EP receptor subtypes demonstrate that PGE2-induced sensitization of sensory neurons is dependent on the EP3C and EP4 receptors (Southall and Vasko, 2001). However, the recent study by use of potent and selective EP agonists (Suzawa et al., 2000; Wise, 2006) suggests that PGE2 acts via EP4 receptors to increase cAMP production. Our present results are consistent with these reports, and they confirm that PGE2 acts via EP4 receptors to increase adenylyl cyclase activity in rat DRG cells. Although it may be possible that other EP subtypes contribute to PGE2-evoked pain signaling, our present in vitro and in vivo results strongly suggest that the EP4 receptor subtype mediates PGE2-induced hypersensitivity in rats.
Here, CJ-023,423 has been further characterized in both acute and chronic models of inflammatory pain. Carrageenan-induced hyperalgesia, a well characterized acute inflammatory pain in rodents, is attenuated by CJ-023,423, an effect that is similar to that seen with a high dose level of the nonselective COX inhibitor piroxicam. In an in vivo model of chronic pain, CFA-induced weight-bearing deficit, CJ-023,423 after CFA injection suppresses the pain response. This compound shows a comparable efficacy to an NSAID (piroxicam) in the hyperalgesic response at the highest dose level tested. However, it should be noted that CJ-023,423 is inferior to piroxicam in terms of in vivo potency and duration of action. In contrast to CJ-023,423, which has a moderate plasma half-life (2.0 h) and low oral bioavailability, piroxicam has superior pharmacokinetic profile with a longer plasma half-life (7.0 h) and much higher oral bioavailability (100%) (Kimura et al., 1997). EP4 receptors are expressed by primary sensory neurons, and EP4 levels increase in the DRG after peripheral inflammation (Oida et al., 1995; Kopp et al., 2004; Lin et al., 2006). Reverse transcription-polymerase chain reaction analysis of the inflamed L5 DRGs by CFA injection shows an increase in only EP4 mRNA, but not in other EP receptors (EP1, EP2, and EP3) (Lin et al., 2006). Thus, EP4 may play a more substantial role in peripheral chronic inflammatory pain because of its increased levels after peripheral inflammation. The genetic inactivation of EP4 using intrathecally delivered short hairpin RNA has demonstrated that the EP4 receptor mediates inflammatory pain hypersensitivity in rats (Lin et al., 2006). EP4 knockdown attenuates CFA-induced thermal and mechanical hypersensitivity. Our present results, using a highly selective EP4 antagonist, are consistent with this recent finding.
In conclusion, EP4 antagonists can effectively attenuate inflammatory pain hypersensitivity in preclinical models of hyperalgesia. EP4 receptor-specific antagonists may, therefore, be useful drugs for the treatment of the signs and symptoms of osteoarthritis and inflammatory pain of various etiologies. EP4 antagonists as new analgesics may have an advantage over other approaches that target prostaglandins such as NSAIDs, COX-2 inhibitors, or prostaglandin synthase inhibitors. This will be determined in part by the specific role of EP4 in other PGE2-mediated functions, such as renal homeostasis, endothelial and platelet function, control of blood pressure, and gastrointestinal mucosal function, which remain to be systematically investigated. The overall safety profile of selective EP4 antagonists should, nevertheless, be different from COX-2 inhibitors and NSAIDs that block PG synthesis of all of the COX products. Targets downstream of COX inhibition, such as selective EP4 antagonism, may therefore provide an opportunity for the development of more specific and better tolerated analgesics beyond COX inhibition.
|
Acknowledgements |
|---|
|
Footnotes |
|---|
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: NSAID, nonsteroidal anti-inflammatory drug; COX, cyclooxygenase; PG, prostaglandin; CJ-023,423, N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide; HEK, human embryonic kidney; DMEM, Dulbecco's modified Eagle's medium; FBS, fetal bovine serum; MES, 2-(N-morpholino)ethanesulfonic acid; EP, prostaglandin E2 receptor; DP, prostaglandin D2 receptor; IP, prostacyclin receptor; FP, prostaglandin F2 receptor; TP, thromboxane A2 receptor; DRG, dorsal root ganglion(ia); SD, Sprague-Dawley; IBMX, 3-isobutyl-1-methylxanthine; CR, concentration ratio; MC, methylcellulose; CFA, complete Freund's adjuvant; ANOVA, analysis of variance; PWL, paw withdrawal latency(ies); PWT, paw withdrawal threshold(s); WBD, weight-bearing difference(s); LT, leukotriene; TNF, tumor necrosis factor; ICI 118551, (±)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol; GBR 12909, 1-{2-[bis-(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine; SCH23390, R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride; D600, (±)-methoxyverapamil; CGS19755, cis-4-[phosphomethyl]-piperidine-2-carboxylic acid; T3, triiodothyronine; U44069
[GenBank]
, 9,11-dideoxy-9, 11-epoxymethanoprostaglandin F2; WEB2086, 4-[3-[(4-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]-1-oxopropyl]-morpholine; ONO-8711, 6-[(2S,3S)-3-(4-chloro-2-methylphenylsulfonyl-aminomethyl)-bicyclo[2.2.2]octan-2-yl]-5Z-hexenoic acid; ZD-6416, 6-[[5-bromo-2-(cyclopropylmethoxy)benzyl](ethyl)amino]-N-(propylsulfonyl)pyridazine-3-carboxamide; AH23848, (4Z)-7-[(rel-1S,2S,5R)-5-((1,1'-biphenyl-4-yl)methoxy)-2-(4-morpholinyl)-3-oxocyclopentyl]-4 heptenoic acid; GW6273678X, N-{2-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetyl}benzene sulfonamide.
Address correspondence to: Dr. Junji Takada, Discovery Biology Research, Nagoya Laboratories, Pfizer Global Research and Development, Pfizer Inc., 5-2 Taketoyo, Aichi, 470-2393, Japan. E-mail: junji.takada{at}pfizer.com
|
References |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Arunlakshana O and Schild HO (1959) Some quantitative uses of drug antagonists. Br J Pharmacol 14: 48–58.
Bing RJ and Lomnicka M (2002) Why do cyclo-oxygenase-2 inhibitors cause cardiovascular events. J Am Coll Cardiol 39: 521–522.
Boie Y, Stocco R, Sawyer N, Slipetz DM, Ungrin MD, Neuschafer-Rube F, Puschel GP, Metters KM, and Abramovitz M (1997) Molecular cloning and characterization of the four rat prostaglandin E2 prostanoid receptor subtypes. Eur J Pharmacol 340: 227–241.[CrossRef][Medline]
Cheng Y, Austin SC, Rocca B, Koller BH, Coffman TM, Grosser T, Lawson JA, and FitzGerald GA (2002) Role of prostacyclin in the cardiovascular response to thromboxane A2. Science 296: 539–541.
Cheng YC and Prusoff WH (1973) Relationship between the inhibition constant (Ki) and the concentration of inhibitor which causes 50 percent inhibition (IC50) of an enzyme action. Biochem Pharmacol 22: 3099–3108.[CrossRef][Medline]
Coleman RA, Grix SP, Head SA, Louttit JB, Mallett A, and Sheldrick RL (1994a) A novel inhibitory prostanoid receptor in piglet saphenous vein. Prostaglandins 47: 151–168.[CrossRef][Medline]
Coleman RA, Smith WL, and Narumiya S (1994b) International Union of Pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes. Pharmacol Rev 46: 205–229.[Medline]
Dannhardt G and Kiefer W (2001) Cyclooxygenase inhibitors–current status and future prospects. Eur J Med Chem 36: 109–126.[CrossRef][Medline]
Ferreira SH and Nakamura M (1979) I-Prostaglandin hyperalgesia, a cAMP/Ca2+ dependent process. Prostaglandins 18: 179–190.[CrossRef][Medline]
Garland A, Jordan JE, Necheles J, Alger LE, Scully MM, Miller RJ, and Ray DW (1995) Hypertonicity, but not hypothermia, elicits substance P release from rat C-fiber neurons in primary culture. J Clin Invest 95: 2359–2366.[Medline]
Graham DJ, Campen D, Hui R, Spence M, Cheetham C, Levy G, Shoor S, and Ray WA (2005) Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclooxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet 365: 475–481.[Medline]
Hinz B and Brune K (2002) Cyclooxygenase-2–10 years later. J Pharmacol Exp Ther 300: 367–375.
Kimura E, Bersani-Amado CA, Sudo LS, Santos RJ, and Oga S (1997) Pharmacokinetic profile of piroxicam 
-cyclodextrin, in rat plasma and lymph. Gen Pharmacol 28: 695–698.[Medline]
Kopp UC, Cicha MZ, Nakamura K, Nusing RM, Smith LA, and Hokfelt T (2004) Activation of EP4 receptors contributes to prostaglandin E2-mediated stimulation of renal sensory nerves. Am J Physiol 287: F1269–F1282.
Lenzer J (2005) FDA advisers warn: COX 2 inhibitors increase risk of heart attack and stroke. BMJ 330: 440.
Lin C-R, Amaya F, Barrett L, Wang H, Takada J, Samad TA, and Woolf CJ (2006) Prostaglandin E2 receptor EP4 contributes to inflammatory pain hypersensitivity. J Pharmacol Exp Ther 319: 1096–1103.
Machwate M, Harada S, Leu CT, Seedor G, Labelle M, Gallant M, Hutchins S, Lachance N, Sawyer N, Slipetz D, et al. (2001) Prostaglandin receptor EP4 mediates the bone anabolic effects of PGE2. Mol Pharmacol 60: 36–41.
McAdam BF, Catella-Lawson F, Mardini IA, Kapoor S, Lawson JA, and FitzGerald GA (1999) Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci U S A 96: 272–277.
Minami T, Nakano H, Kobayashi T, Sugimoto Y, Ushikubi F, Ichikawa A, Narumiya S, and Ito S (2001) Characterization of EP receptor subtypes responsible for prostaglandin E2-induced pain responses by use of EP1 and EP3 receptor knockout mice. Br J Pharmacol 133: 438–444.[CrossRef][Medline]
Minami T, Nishihara I, Uda R, Ito S, Hyodo M, and Hayaishi O (1994) Characterization of EP-receptor subtypes involved in allodynia and hyperalgesia induced by intrathecal administration of prostaglandin E2 to mice. Br J Pharmacol 112: 735–740.
Moriyama T, Higashi T, Togashi K, Iida T, Segi E, Sugimoto Y, Tominaga T, Narumiya S, and Tominaga M (2005) Sensitization of TRPV1 by EP1 and IP reveals peripheral nociceptive mechanism of prostaglandins. Mol Pain 1: 3.[CrossRef][Medline]
Murata T, Ushikubi F, Matsuoka T, Hirata M, Yamasaki A, Sugimoto Y, Ichikawa A, Aze Y, Tanaka T, Yoshida N, et al. (1997) Altered pain perception and inflammatory response in mice lacking prostacyclin receptor. Nature 388: 678–682.[CrossRef][Medline]
Nakayama Y, Omote K, and Namiki A (2002) Role of prostaglandin receptor EP1 in the spinal dorsal horn in carrageenan-induced inflammatory pain. Anesthesiology 97: 1254–1262.[CrossRef][Medline]
Nasrallah R and Hebert RL (2005) Prostacyclin signaling in the kidney: implications for health and disease. Am J Physiol 289: F235–F246.
Oida H, Namba T, Sugimoto Y, Ushikubi F, Ohishi H, Ichikawa A, and Narumiya S (1995) In situ hybridization studies of prostacyclin receptor mRNA expression in various mouse organs. Br J Pharmacol 116: 2828–2837.[Medline]
Omote K, Kawamata T, Nakayama Y, Kawamata M, Hazama K, and Namiki A (2001) The effects of peripheral administration of a novel selective antagonist for prostaglandin E receptor subtype EP(1), ONO-8711, in a rat model of postoperative pain. Anesth Analg 92: 233–238.
Reinold H, Ahmadi S, Depner UB, Layh B, Heindl C, Hamza M, Pahl A, Brune K, Narumiya S, Muller U, et al. (2005) Spinal inflammatory hyperalgesia is mediated by prostaglandin E receptors of the EP2 subtype. J Clin Invest 115: 673–679.[CrossRef][Medline]
Sarkar S, Hobson AR, Hughes A, Growcott J, Woolf CJ, Thompson DG, and Aziz Q (2003) The prostaglandin E2 receptor (EP-1) mediates acid-induced visceral pain hypersensitivity in humans. Gastroenterology 124: 18–25.[CrossRef]
Solomon SD, McMurray JJ, Pfeffer MA, Wittes J, Fowler R, Finn P, Anderson WF, Zauber A, Hawk E, and Bertagnolli M (2005) Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 352: 1071–1080.
Southall MD and Vasko MR (2001) Prostaglandin receptor subtypes, EP3C and EP4, mediate the prostaglandin E2-induced cAMP production and sensitization of sensory neurons. J Biol Chem 276: 16083–16091.
Stock JL, Shinjo K, Burkhardt J, Roach M, Taniguchi K, Ishikawa T, Kim HS, Flannery PJ, Coffman TM, McNeish JD, et al. (2001) The prostaglandin E2 EP1 receptor mediates pain perception and regulates blood pressure. J Clin Invest 107: 325–331.[Medline]
Suzawa T, Miyaura C, Inada M Maruyama T, Sugimoto Y, Ushikubi F, Ichikawa A, Narumiya S, and Suda T (2000) The role of prostaglandin E receptor subtypes (EP1, EP2, EP3, and EP4) in bone resorption: an analysis using specific agonists for the respective EPs. Endocrinology 141: 1554–1559.
Ueno A, Matsumoto H, Naraba H, Ikeda Y, Ushikubi F, Matsuoka T, Narumiya S, Sugimoto Y, Ichikawa A, and Oh-ishi S (2001) Major roles of prostanoid receptors IP and EP(3) in endotoxin-induced enhancement of pain perception. Biochem Pharmacol 62: 157–160.[CrossRef][Medline]
Wilson RJ, Giblin GMP, Roomans S, Rhodes SA, Cartwright K-A, Shield VJ, Brown J, Wise A, Chowdhury J, Pritchard S, et al. (2006) GW627368X ((N-{2-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo isoindol-2-yl)phenyl]acetyl} benzene sulphonamide): a novel, potent and selective prostanoid EP4 receptor antagonist. Br J Pharmacol 148: 326–339.[CrossRef][Medline]
Wise H (2006) Lack of interaction between prostaglandin E2 receptor subtypes in regulating adenylyl cyclase activity in cultured rat dorsal root ganglion cells. Eur J Pharmacol 535: 69–77.[CrossRef][Medline]
Zhang Y, Shaffer A, Portanova J, Seibert K, and Isakson PC (1997) Inhibition of cyclooxygenase-2 rapidly reverses inflammatory hyperalgesia and prostaglandin E2 production. J Pharmacol Exp Ther 283: 1069–1075.
This article has been cited by other articles:
|
|
 |
|
  D. Xu, S. E. Rowland, P. Clark, A. Giroux, B. Cote, S. Guiral, M. Salem, Y. Ducharme, R. W. Friesen, N. Methot, et al. MF63 [2-(6-Chloro-1H-phenanthro[9,10-d]imidazol-2-yl)-isophthalonitrile], a Selective Microsomal Prostaglandin E Synthase-1 Inhibitor, Relieves Pyresis and Pain in Preclinical Models of Inflammation J. Pharmacol. Exp. Ther., September 1, 2008; 326(3): 754 - 763. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Clark, S. E. Rowland, D. Denis, M.-C. Mathieu, R. Stocco, H. Poirier, J. Burch, Y. Han, L. Audoly, A. G. Therien, et al. MF498 [N-{[4-(5,9-Diethoxy-6-oxo-6,8-dihydro-7H-pyrrolo[3,4-g]quinolin-7-yl)-3-methylbenzyl]sulfonyl}-2-(2-methoxyphenyl)acetamide], a Selective E Prostanoid Receptor 4 Antagonist, Relieves Joint Inflammation and Pain in Rodent Models of Rheumatoid and Osteoarthritis J. Pharmacol. Exp. Ther., May 1, 2008; 325(2): 425 - 434. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|
 |
 |
 |
