sign in sign up
<<
Home , Latanoprost, Prostaglandin G2

Celltransmissions The Newsletter for and Neuroscience Research

Vol 20, No 2 • June 2004

New Products pp. 12-14 In this Issue... Monoclonal Anti-γ Parvin: Focal adhesion protein p. 9 S(–)-Blebbistatin: Non-muscle An Update on Ligands for Receptors myosin II inhibitor p. 9 Robert Jones APHA Compound 8: Histone deacetylase inhibitor p. 9 17-AAG: Potent Hsp90 he natural arise from the activity female reproductive tracts [2]. PGE2 and PGF2α inhibitor p. 10 of intracellular cyclo-oxygenase (COX) on were shown to be potent stimulants of uterine T Ro 48-8071: 2,3-Oxido- polyunsaturated fatty acids released from mem- smooth muscle and this triggered further squalene:lanosterol cyclase brane phospholipids. In the case of the most research into their roles in normal parturition. In inhibitor p. 10 important substrate, (20:4ω6), addition, analogs were synthesized for the safe Anti-FKHR: Transcription the first product is G2 (PGG2), induction of parturition. PGF2α was also found factor marker p. 10 which is then reduced to PGH2 by an associated to induce luteolysis in many laboratory and farm 15-hydroperoxidase [1]. Depending on the animals, and in some species has been shown to OMPT: LPA3 lysophosphatidic tissue, PGH2 may be further metabolized by iso- function as a uterine luteolytic hormone [3]. acid p. 11 merases to PGD , PGE , PGI ( and Thus, following release from the uterus, PGF2α 2 2 2 SB-239063: p38 MAP kinase TXA2 and by a reductase to PGF2α. induces regression of the corpus luteum, a fall in progesterone level and termination of the estrus inhibitor p. 11 cycle. The therapeutic potential of this mecha- Anti-Tuberin (IA-22): Protein The natural prostanoids perform a variety of nism for post-coital contraception and the induc- product of the tumor physiological and pathological roles. The discov- tion of abortion was soon recognized. However, suppressor gene TSC2 p. 11 ery of several E and F at particu- the role of research interest waned with the Bohemine: cdk inhibitor p. 11 larly high concentrations in human semen stimu- realization that luteal regression in the human lated interest in their actions on both male and female is somewhat different to that in lower RHC 80267: inhibitor p. 15

continued on page 3 ACE inhibitors p. 15 Application Note: Monoclonal Anti-EPCR: Protein C anticoagulation pathway marker p. 15 Improved Ex Vivo Expansion of Functional MRS 2395: P2Y12 purino- CD34+ Cells Using Stemline™ II Hematopoietic ceptor antagonist p. 16 SB-258585: 5-HT6 serotonin Stem Cell Expansion Medium receptor antagonist p. 16 Anti-Transportin 1: Nuclear Daniel W. Allison, Stacy L. Leugers, Barry J. Pronold, Gary Van Zant, import receptor marker p. 16 and Laurel M. Donahue Chrysamine G and BTA-1: β-amyloid aggregate probes p. 17 Introduction VDM11: Anandamide mem- ematopoietic stem cells (HSC) have the ability to repopulate the brane transport inhibitor p. 17 Hhematopoietic system by differentiating into all of the necessary URB597: amide erythroid, lymphoid, and myeloid lineages. Due to this rare ability, HSCs hydrolase (FAAH) inhibitor p. 17 are used as therapeutic agents in the treatment of malignant and benign New Phosphorylation Assay diseases of the blood forming and immune systems. There have been Kits pp. 18-19 many advances in the area of clinical HSC research, but the availability of suitable cells for transplantation still remains a major limiting factor [1,2].

continued on page 20 sigma-aldrich.com/cellsignaling each denotedbyasubscriptnumeral(i.e.EP Further studiesdividedtheEPreceptor intofoursubtypes, • • matory effects ofPGE vessel, whileathigherdosesitsuppresses thepro-inflam- of prostacyclin,whichcouldbeformedfomPGH cular disease.Furtherimpetuswasaddedbythediscovery cells stimulatedenormousinterestinitsolecadiovas- activate thistissueandadjacentvascularsmoothmuscle arachidonate metabolisminhumanplatelets[6],couldalso irreversibly inhibitsTXA acid, Prod.No. the uniquetherapeuticprofileof ing tovariouspathologicalstates.Aroundthesametime, emerged ofanimbalancebetweentheseagentscontribut- Prostacyclin hadopposingactionstoTXA vessels andwasalsounstableinphysiologicalmilieu[7,8]. general, DP, EP common PGEancestor hasbeenpostulated[12,13]. In of Gprotein-coupled receptors, andtheir evolutionfrom a Prostanoid receptors belong totherhodopsinsuperfamily EP • [10], basedonthree experimental approaches: prostanoid receptor, referred toasDP, EP, FP, IPandTP this wasthestartingpointfordefiningfivetypesof exhibit distinctivepharmacologicalprofiles. Inthe1970s It thusbecameclearthatthefiveprimaryprostanoids Classification ofProstanoid Receptors order animals. compromising theprotective valueofPGI The demonstrationthatTXA subject ofmajornewdevelopments(seelater). allergen-induced disease[5].Thelatterprofilehasbeenthe implicated inthecontrolofsleep[4]andasamediator some 40yearsafterthediscovery ofPGE receptor andsomeEPreceptors are onlynowemerging although itissurprisingthatuseful antagonistsfortheFP antagonists withhigheraffinity andspecificitycontinued, venient celllines[11].Inaddition,thedevelopmentof the eightprostanoid receptors, andtheirexpression incon- came through theisolationandstructuraldeterminationof In thelate1990s,verificationofthisclassificationsystem Robert Jones An UpdateonLigandsforProstanoid Receptors low. some casesthespecificityofantagonistwasrelatively The useofcompetitivereceptor antagonists,althoughin appropriate affinity rankingsforcompetingligands identify saturablebindingsitesoncellmembraneswith The useofradiolabeledprostanoids (e.g.[ signifies aDPreceptor) preparations (e.g.PGD The rankingofagonistpotenciesonisolatedtissue 4 ). PGD 2 A 5376 , EP 2 4 has hadachequeredcaee,being and IPreceptors coupletoadenylyl 2 ) becameapparent:atlowdosesit 2 similar tootherCOXinhibitors[9]. biosynthesis inplateletswithout 2 > PGF 2 , ahighlylabileproductof 2 α > PGE 2 2 (acetyl salicyclic 2 2 and theconcept on theblood and PGF = PGI 3 1 H]-PGE , EP 2 2 2 = TXA , EP in blood 2 2 α ) to . 3 and 2 through RNAsplicingandusuallycoupletoG complex molecularbiology. Theyexistinseveralisoforms and TPreceptors coupletophospholipaseCviaG (e.g. SQ27986) [23]alsoleadstoselectiveDP . cyclin analogs(e.g. RS-93520)[21,22]andPGH analogs Inversion ofallchiralcentersin theringsystemsofprosta- may existas9-oxo,11-oxoand 9,11-dioxotautomers. has beenwidelyusedasaselective DPagonist[18-20];it nist activity.Thehydantoin cyclase viaG ral agonist,althoughnon-prostanoid agonistsexistforEP They oftenbearaclosestructuralresemblance tothenatu- ual isoformsmayalsocoupletoG the naturalprostanoid (PGD tors, anS-configurationforthe C15-secondaryalcoholin plasma exudation[17].Similartootherprostanoid recep- tion [15],relaxation ofvascularsmoothmuscle[16]and The DPreceptor mediatesinhibitionofplateletaggrega- sigma/rbi-handbook/sg_ls_cs_rbibook_prostanoid.pdf Sigma-RBI Handbook-seehttp://www.sigma-aldrich.com/ also referred tothe‘Prostanoid Receptors’chartinThe prostanoid receptors willbebrieflydiscussed.Thereader is cloned prostanoid receptors. Usefulligandsforeach of the recently from highthroughput screening assaysusing chemical modificationofapartialagonist,andmore and IPreceptors. Antagonistshaveemergedfrom the case ofPGI been designedinitiallytoresist metabolism,andinthe Synthetic agonistsforeachprostanoid receptor have often produce excitatoryevents.EP Antagonist 11 Agonists H O 9 O O (Prod. 2 N SQ 27986 SQ O O s PGD and TXA No. (Prod. to produce inhibitoryevents,whileEP O 5 N H

15 O P 5172) 2 BW A868C BW H H N No. Figure 1. DP Receptor Ligands COO O

2 B COO 1 H

to bechemicallystableaswell. 9180 H H CH ) BW 245C COO 2 3 ) iscriticallyimportanttoago- 3 receptors havethemost H H (continued fromcover) q N O O , G N (Prod. No. s O RS 9352 and G COO H (Prod. H O BW 245C BW

H 0 No. i 12,13 , butindivid- O

H B 9305) B 9305 COO q [14]. to 1 , FP H ) 3

Celltransmissions Vol 20, No. 2, 2004 Order: 1-800-325-3010 Technical Service: 1-800-325-5832 sigma-aldrich.com/cellsignaling

¨

Update on Ligands for 3 ¨ Prostanoid Receptors ¨

Update on Ligands for 4 ¨ Prostanoid Receptors

Celltransmissions Vol 20, No. 2, 2004 Order: 1-800-325-3010 Technical Service: 1-800-325-5832 sigma-aldrich.com/cellsignaling Antagonists ly more stable13,14-dihydro-15-oxo PGD indomethacin potent agonistactivitiesof15-oxoPGD in colonicmucosa[29].Amajordiscriminatingfactoristhe constriction [27,28]andsuppression ofshort-circuit current receptor orFPandTPreceptors; twoexamplesare arterial effects thatcannotbeattributedtoeithertheclassicalDP It hasbeenknownforsometimethatPGD response curveforPGE 5.1) mayresult inaright-shiftoftheconcentration- behaves competitively(pA proved usefulinidentifyingDPreceptors [20,24,25]. It The DPantagonistBWA868C,arelative ofBW245C,has Ligands forProstanoid Receptors... PGD cells, eosinophilsandbasophils,whenactivatedby receptor, andispreferentially expressed inThelpertype2 related tochemoattractant receptors suchasthefMLP been isolatedfrom amouse genomiclibrary[30,31].Itis withasimilaragonistprofileon TH2cells(CRTH2) has chemoattractant receptor-homologous molecule expressed classical receptor. Recently, anovelreceptor identifiedas specificity. However, itsaffinity fortheEP highly sensitiveEP H Agonists (Prod. O O O 2 ONO 871 ONO N leads toeosinophilactivation.TheCOXinhibitor H PGE O No. S H 3

C P 2

5640) 1 COO H O O O H (Prod. No. H 4 H C systems [26]. O (Prod. 3 l (Prod. N C Figure 2. EP ONO-DI-004 COO 2 O SC 19220 SC in bloodvesselpreparations with No. N H 2 I 7378 H O CH 7.8 -9.5)andshowsgood NH

H O 01889)

C S N 3

l 3065 1 H Receptor Ligands COO ) isanagonistforthe O O O ) O H C l H 2 N O N 4 and thechemical- ω 17-Phenyl 2 O SC 51322 SC N -trinor PGE receptor (pA 2 on thenon- H CH induces O 3 H S 2 COO 2 (continued) H O including , isocarbacyclin( selective EP The firstEP receptor [44]. Anon-prostanoid EP although itdoespossessmeasurable affinity fortheDP being usedinpreference tobutaprost asitismore potent, Recently, a6-oxoPGE described asanEP potency, EP receptors insometissues.AH13205isaselective,butlow- acid mayconfoundthediscrimination ofEP methyl estertoproduce thebiologicallymore activefree agonist formanyyears,butslowde-esterificationofitsC1- can beusedtodiscriminateEP are alsopotentEP these showpotentialasanalgesics.CertainPGHderivatives tive congenershavefollowed(e.g.SC51322)[38,39],and SC 19220 Some prostacyclinanalogsaealsopotentEP has recently beenreported [45]. (Prod. No. bronchial andreproductive smoothmuscles. (Prod. No. more selective,andincombinationwith Activation ofEP are somebiphenylenedibenzazocinones [41]. and trachea. 16,16-DimethylPGE activation causescontractionofsmoothmuscleingutand EP immunological diseases. ing antagonistsforthisreceptor astherapeuticagentsfor require reconsideration. There ismuchinterest indevelop- biosynthesis inisolatedtissuesystemsmaytherefore receptorCRTH2 [32]; itsroutine usetosuppress prostanoid Agonists H 1 Antagonis H O O receptors havealimitedtissuedistribution,andtheir carbacyclin 3 C CH (Prod. (R)-Butaprost O 3 (Prod. (Prod. No. B 6309 S 8692 1 1 2 t

No. antagonist wasthedibenzoxazepine-hydrazide agonist [33],while17-phenyl- agonist [43].ONO-AE1-259is increasingly AH 6809 AH

No. 2 H B 6309) O (6a-carba PGI receptors leadstorelaxation ofvascular, ) (EP 1 ) [42]hasbeenusedasaselectiveEP

O O 1 A -selective agonist[35,36]. antagonists (e.g.ONO8711)[40],as

Figure 3. EP 1221 S 3065 1 3 analog, ONO-DI-004,hasbeen COOCH > EP ) COO O 1 ) [37].Morepotentandselec- CH 2 ) andSC-46275(EP 3 2 1 is ahighlypotentbutnon- 2 Receptor 3 H H ; Prod.No. and EP O C ∆ l 2 6,6a (Prod. agonist, CP-533,536, ONO-AE1-259 -6a-carba PGI 3 AH 13205 AH O

receptors [34]. No. H ω C 3305 2

A 9102) -trinor PGE Butaprost 1 H s and EP O COO agonists, 3 H )) [34]. >> EP CH 1 4 ) [33] COO 3 2 2 1 H is ) H H is apotentEP hydrolysis ofitsC1 SC-46275 ismore potent and more selective[49,50];again [48]; ithasbeenusedtocontrol post-partumhemorrhage. DP andEP brain. Sulprostone isthemost commonlyusedEP of feverwheninjectedintotheventricularsystem gut, enhancementofplateletaggregation, andinduction lipolysis andgastricacidsecretion, cytoprotection inthe including vascularanduterinesmoothmuscle,inhibitionof ied. Inbrief,itmediatescontractionofsmoothmuscle, tiple couplingcapacitymeansthatitspharmacologyisvar- The EP as 10 EP Selective antagonistsfortheEP Ligands forProstanoid Receptors... figure 7)isanEP ONO-AP-324 (cfnon-prostanoid prostacyclin mimeticsin can beusedtoinduceabortion[53].Thenon-prostanoid terone antagonist susceptible individuals.Incombinationwiththeproges- inhibitor therapytoreduce gastricirritationandbleedingin potent thanSC-46275[51]. PGE instances. ONO-AE-248,the11,15-bis-methyletherof perhaps accountingforitsslowonsetofactioninsome threshold relaxation seenatconcentrations ofPGE EP to appearintheliterature [55]. number ofEP some preparations [54].Incontrasttotheavailabilityof a human EP able. ThexanthonecarboxylicacidAH6809doesblock O O Agonists O O 4 2 2 systems inbloodvesselsare oftenhighlysensitive,with and EP , isalsoaselectiveEP -11 (Prod. 3 (Prod. NM receptor hasawidetissue distributionanditsmul- Sulprostone M [56].Selective EP 2 1

4 No. S H receptors [46],butithassimilar affinities for receptors [47,48]. O receptors [52].ItisusedasanadjuncttoCOX O H 3 3 agonists, EP agonist, butalsodisplaysagonistactivityat

8692 CH 3 O

mifepristone 6932 agonist thatexhibitspartialagonismon - 3 methyl estermayoccurwithintissues, ) CONHSO COOCH Figure 4. EP ) 3 Misoprostol 3 3 agonist, butappearstobeless 4 2 antagonists are justbeginning H CH agonists havenot beenavail- O O 2 3 O OCH 3 ReceptorLigands receptor are notyetavail- (Prod. No. 3 ONO-AE-248 (Prod. No. H SC 46275 SC O OCH M 8046 CH 3 3 3 M 6932 2 agonist COOCH ), it as low COO H (continued) 3 ) H 3 C enantiomer offluprostenol () hasrecently been parturition infarm animals.Theisopropyl esterofthe(+)- and are used tosynchronize estrusand induce although itsaffinity islow(pA potent andselectiveEP Modification oftheterminalfive-carbonunitinPGF L-161,982 [59],ONO-AE3-208[60]andGW627368[61]. [58] hasfoundconsiderableutilityasanEP The TPreceptorantagonist nists, forexample,AFP-07andcicaprost [39,57]. able untilrecently; ONO-AE1-329 hasaK potent, non-selectiveEP while the16-p-fluorophenoxy analog(ICI799390)isa substitution (cloprostenol) issomewhatlessfavorable, F 8549 romethylphenoxy moiety(asin matically altersagonistselectivity[62-64].A16- Some prostacyclin analogsare moderatelypotentEP 10,000 nMfortheothermouseprostanoid receptors [35]. the recombinant mouseEP O Antagonist Agonist S O N ) confershighFPselectivity;16- O L-161,982 O (Prod. s H N O H O O O AH 23848 AH S

No. O N N Figure 5. EP

A N S

8227) ONO-AE1-32 CF 4 1 CO antagonists havebeendescribed; , FPandTPagonist.Fluprostenol 3 O 4 1/2Ca O H AH 23848 4 receptor andgreater than Receptor Ligands S 2 2 + CH fluprosteno 5.4) [56].Recently, several N 9 3 COO C H O m (Prod. No. GW 627368 S -chlorophenoxy i ONO-AE3-20 O O O of 10nMfor 4 H N O O l, Prod. No. antagonist, N H O m N A 8227 -trifluo- COO 2 4 8 α ago- dra- O H ) F

Celltransmissions Vol 20, No. 2, 2004 Order: 1-800-325-3010 Technical Service: 1-800-325-5832 sigma-aldrich.com/cellsignaling

¨

Update on Ligands for 5 ¨ Prostanoid Receptors 6 Ligands for Prostanoid Receptors...(continued)

Figure 6. FP Receptor Ligands Early work on the EP series of TP antagonists showed that a diphenylmethoxime moiety in the ω-chain conferred IP Agonists COOH COOH agonist activity (e.g. EP 157) [74]. Other studies on analogs of octimibate, an ACAT (acyl-CoA: cholesterol acyltrans- HO HO ferase) inhibitor [75], and 3,7-m-interphenylene-3-oxa

PGE1 [76] further established the importance of a 1,1- or 1,2-diarylheterocyclic group situated at a critical distance O from the C1-carboxylate for IP agonist activity. These non- O H OH HO OH prostanoid prostacyclin mimetics were initially thought to Fluprostenol PGF α CF3 2 (Prod. No. F 8549) be more effective inhibitors of activation than (Prod. No. P 0424) vasodilators. However, this appears not to be the case, and COOCH(CH3)2 they probably do not represent a therapeutic advance over HO prostacyclin and its close analogs in producing less systemic blood pressure depression at doses that suppress platelet activation and relieve pulmonary hypertension. BMY 45778 is the most potent of the non-prostanoids (77). Care is

HO OH needed in using these agents to characterize IP receptors, since some of them inhibit PLC-dependent events via a (Prod. No. L 1167) mechanism independent of IP receptors [78]. Several IP

Partial Agonist COOH receptor antagonists that are structurally unrelated to prostacyclin have recently been described in the patent

Prostanoid Receptors Prostanoid HO literature [79]. Update on Ligands for

Figure 7. IP Receptor Ligands Agonists

COOH COOH F OH O AL-8810 (Prod. No. A 3846)

marketed for the treatment of [65]. Other PGF O analogs with a similar clinical usage include latanoprost (Prod. No. L 1167) and . It is generally assumed that these agents are lipophilic pro-drugs, and that after topical administration hydrolysis occurs within the eye to HO HO give the corresponding free acid as the more potent FP OH OH agonist [66]. However, in the case of bimatoprost, it has PGI2 been proposed that the C1-ethyl amide remains intact with- (Prod. No. P 6188) Cicaprost in the eye and that a discrete receptor may be involved [67]. COOH COOH O The PGF analog AL-8810 (Prod. No. A 3846) is a partial agonist at FP receptors [68], and may represent a promis- ing lead for the development of an FP antagonist. O F N The vinyl ether in prostacyclin is readily hydrated under F O physiological conditions, resulting in loss of its characteris- tic platelet-inhibition and vasodilator activities. The proton N HO initially added to C5 may derive from the C1-carboxyl OH ONO-1301 (Prod. No. O 2264) group or from the medium. Reducing negativity at C5 by AFP-07 appropriate substitution of fluorine confers high acid stabil- Partial Agonist COOH ity; one such agent AFP-07 is the most potent IP agonist COOH reported to date [57,69]. Replacement of the 6a-oxygen with methylene is another stabilization strategy; these car- O bacyclins include carbacyclin itself [70], iloprost [71] and V ol 20, No. 2, 2004 O r der: 1-800-325-3010 T echnical Service: 1-800-325-5832 s igma-aldrich.com/cellsignalin g cicaprost [72]. Cicapost is a reasonably selective IP agonist O

¨ [33] and has been used in many characterization studies. O Steric hindrance to internal protonation is found in O

taprostene (Prod. No. T 4949), which has a meta-benzene N N ¨ ring inserted between C1 and C5 [73]; it behaves as a HO OH partial agonist at the IP receptor [57]. BMY 45778 Taprostene Celltransmissions (Prod. No. T 4949) Antagonists Agonists Ligands forProstanoid Receptors... both are activatedbyTXA carboxyl-terminal sequencehavebeenidentified[80],and PGH agonists are common,forexample,9,11-epoxymethano used TPagonistincharacterization studies[82].Partial 11,9-epoxymethano PGH Many stableringanalogshavebeensynthesized,including more dangerous accumulationinthesystemiccirculation. agonists permitslocalhemostasis,whilelesseningtheir The highinstabilityandrapidmetabolismofthenatural ( and bronchoconstriction. Inhumanplatelets,twoisoforms TP receptors mediateplateletaggregation, resistant to deactivationby15-hydroxyprostaglandin dehy- (e.g. EP171,I-BOP) [86,87],andalsorenders themolecule substitution onPGH As withICI79939inthePGFseries, 16- α O O O and C H l 2 O O , CTA β ) oftheTPreceptor thatare divergentinthe (Prod. (Prod. (Prod. (Prod. 2 N O and PTA R32191 GR S Daltroban U-46619 NH

No. No. O

No. PGH No. P O O

H H

G D

D

2

5044) 7441

2

8174) 2 786) Figure 8. TP Receptor Ligands /TXA [83,84]); STA ) COO COO 2 2 2 (U-46619), themostcommonly COO analogs enhancesTPagonism and itsprecursor PGH COO H H H H S O O 2 F O [85] isafullagonist. C l (Prod. p -halophenoxy L-655,240 N H No. STA N O TXA O H N SQ-29548

H L 9539) H 2 2 O 2 [81]. H N COO COO COO (continued) COO H H H H activity intheseareas: EP following examplesillustratethecontinuingandintense development oftrulyselectivereceptor ligands.The prostanoid receptor gene-knockoutmice[96],andthe protein/mRNA levelsindisease states,theuseof promised basedontheprevalence ofprostanoid receptor of glaucomaare twoexamples. Furtheradvancesare antagonists. be achievedwithabatteryofhighly selectiveprostanoid ing thelocalinterplayofnaturalprostanoids canonly diseases are immenselycomplexhowever, andinvestigat- bumen challenge[100].Inflammatoryandimmunological associated withareduced inflammatoryresponse tooval- knockout mouse[98];EP femoral boneformationinwild-typeandEP [97]; localapplicationofaselectiveEP .Horton, E.W., Poyser, N.L., 3. Moore, P.K. “Biosynthesisandcatabolismof prostaglandins, 2. Wise,H.,Jones,R.L., “Anintroductiontoprostacyclinanditsreceptors.”In: 1. References receptor knockoutmice,butnotintheEP been significantadvances:PGI disease were unrealistically high.Nevertheless,there have The earlyexpectationsforprostanoids inthetreatment of Conclusions while othersarenot,e.g. (Vapiprost; Pod.No. prostanoid instructure, e.g.EP092,S-145, cal developmentinthe1980s.Manyantagonistsare treatment ofthrombotic disorders triggered intensechemi- The obvioustherapeuticpotentialofTPantagonistsinthe an organicsolvent. great care inthelaboratory, especiallywhendissolvedin drogenase. Thistypeofmoleculeshouldbehandledwith monary hypertensionandPGF colitis intherat,whileEP the developmentofdextransodiumsulphate-induced for anEP pathological role forPGE susceptibility tothromboembolism [99]pointingtoa myocardial infarction patients[95]. ONO-1301). Ofthese,Ridogrel hasshownbenefitinpost- priately positionedimidazolylor inhibition are known[92]; theyusuallycontainanappro- that showbothTPreceptor antagonismandTXsynthase therapy forvariouscardiovascular diseases[9].Compounds anticipated duetotheemergenceoflow-doseaspirin apeutic applicationofTPantagonistshasbeenlessthan simple competitioninsomepreparations [93,94].Thether- agents, e.g.BMS180291andGR32191,deviatefrom usually obtained,althoughsomeofthemore potent cy andspecificity. Asurmountablereversible blockadeis most commonlyusedantagonistsduetotheirhighpoten- and L-655,240)[92].GR32191SQ29538are the Clinical Relevance,pp 1-40;CambridgeUniversityPress, (1985). and ”.In: Prostanoids:Pharmacological,Physiological and Prostacyclin anditsReceptors,pp1-27;Kluwer Academic,NewYork (2000). 3 antagonist; finally, EP G 5044 Physiol. Rev., 2 3 4 2 Daltroban and apossibletherapeuticuse receptor deletiondecreased mRNA markedlyincreased with mRNA showedlittlechange ) andSQ29538)[88-91], 2 2 α 56 2 in thetreatment ofpul- m analogs inthetreatment , 595-651(1976). receptor knockoutwas -pyridyl group (e.g. (Prod. No. 4 agonist increased 4 receptor GR 32191 1 , EP D 7441 2 and EP ) 3

Celltransmissions Vol 20, No. 2, 2004 Order: 1-800-325-3010 Technical Service: 1-800-325-5832 sigma-aldrich.com/cellsignaling

¨

Update on Ligands for 7 ¨ Prostanoid Receptors ¨

Update on Ligands for 8 ¨ Prostanoid Receptors

Celltransmissions Vol 20, No. 2, 2004 Order: 1-800-325-3010 Technical Service: 1-800-325-5832 sigma-aldrich.com/cellsignaling 3 Dong,Y.J., etal., 33. Hirai,H.,etal., 32. 2 Crider, J.Y., etal., 22. Alvarez,R.,etal., 21. 0 Giles,H.,etal., 20. Hatae,N.etal., 14. 0 Kennedy, I.,etal., 10. PatronoC,Roth,G.J., 9. Johnson,R.A.,etal., 8. 6 Okada,Y., etal., 36. Suzawa,T., 35. Lawrence,R.A.,etal., 34. Hirai,H.,etal., 31. 0 Hirai,H.,etal., 30. 5 Hamid-Bloomfield,S.,etal., 25. Trist, D.G.,etal., 24. 3 Seiler, S.,etal., 23. 9 Whittle,B.J., 19. Town, M.H.,etal., 18. Flower, R.J.,etal., 17. Toda, N., 16. Nishizawa,E.E.,etal., 15. 3 Toh, H.,etal., 13. Regan,J.W., etal., 12. Narumiya,S.,FitzGerald,G.A., 11. F 8549 D 4565 D 4143 D 7441 C 3305 B 6309 B 9180 B 9305 B 5806 A 3846 A 1221 A 8227 A 9102 P 7291 P 5539 P 5164 Sigma-RBI Prostanoid Products Available from Bunting,S.,etal., 7. Hamberg,M.,etal., 6. Kabashima,K.,Narumiya,S., 5. Obal,F. Jr., Krueger, J.M., 4. Ligands forProstanoid Receptors... 8 Hallinan,E.A.,etal., 38. Sanner, J.H., 37. 9 Rangachari,P.K., Betti,P.A., 29. Jones,R.L., 28. Jones,R.L., 27. 6 Lydford, S.J.,etal., 26. 1 Ruel,R.,etal., 41. Watanabe, K.,etal., 40. 9 Abramovitz,M.,etal., 39. 0 Tsai, B.S.,etal., 50. 2 Gardiner, P.J., 42. 3 Bygdeman,M.,Danielsson,K.G., 53. Kiriyama,M.,etal., 52. Yokotani, K.,etal., 51. 9 Savage,M.A.,etal., 49. Coleman,R.A.,etal., 48. 6 Woodward, D.F., etal., 46. Li,M.,etal., 45. Cao,J.,etal., 44. Nials,A.T,. etal., 43. 7 Keery, R.J.,Lumley, P., 47. Fluprostenol 2,3-di-nor-8-Isopostaglandin F Ketoprostaglandin F 13,14-Dihydro-15- Daltroban Carbacyclin (R)-Butaprost BWA868C BW245C BM-531 AL-8810 AH 6809 AH 23848 AH 13205 Anti- B Anti-Prostaglandin F Anti- Prostaglandins Acta Biol.Med.Germ Adv. Prost.Thromb.Res Endocrinology Arch. Int.Pharmacodyn.Ther. J. BoneMiner. Res., Prostaglandins Eur. J.Pharmacol. Br. J.Pharmacol. FEBS Lett Bioorg. Med.Chem.Lett. J. Immunol. Br. J.Pharmacol. Biochem. Biophys.Res.Commun. J. Exp.Med Prostaglandins J. Pharmacol.Exp.Ther. J. Biochem Br. J.Pharmacol. Br. J.Pharmacol Br. J.Pharmacol. Br. J.Pharmacol Br. J.Pharmacol Prostaglandins Prostaglandins Prostaglandins Br. J.Pharmacol. Prostaglandins Mol. Pharmacol. Prostaglandins Eur. J.Pharmacol. Br. J.Pharmacol. Prost. Leukot.Essent.FattyAcids, Adv. Prost.Thromb.Leukot.Res Prostaglandins Bioorg. Med.Chem. Cancer Res. Adv. Prost.Thromb.Leukot.Res Stroke Br. J.Pharmacol Br. J.Pharmacol., Prostaglandins , ., Biochim. Biophys.Acta Prostaglandins 23 , 361 Front. Biosci., 141 ., ., , 99-112(1982). , , 168 25 , 131 Am. J.Physiol 193 , 17-21(1995). rs.Luo.Esn.FattyAcids Prost. Leukot.Essent. Br. J.Pharmacol , , 27 , 1554-1559(2000). , , 205-223(1983). 40 87 , J. Clin.Invest. , 981-985(2002). 442 , ., , 756-760(1996). , 781-784(2002). , ., 18 , 255-261(2001). , , ., 96 , , ., , , 119-130(1990). 42 , 45-56(1986). , 12 59 Drugs 24 2 37 2 131 ., 25 2 96 102 87 , 2 52 , 2033-2042(2003). , 127 , α , 291-300(1989). α , 115-123(2002). 56 , 105-109(1991). 1 , , 897-913(1976). 46 , 5093-5096(1999). , 667-689(1982). 12 , 837-844(1978). , , 13-28(1983). , 301-306(1989). , , 97-107(1986). , 125-139(1996). , 221-230(1976). 122 , ., 9 , 745-755(2000). 459 , 24P(1991). , 229-233(1976). , , 204-210(1999). , 213-220(1994). , 915-928(1976). 46 , 109-121(1975). , , 105 94 8 275 9 , 62 , 520-550(2003). , , 217-224(1997). , 371-383(1995). , 187-193(2003). ., , 2699-2704(1999). 9 , 745-754(1988). 180 , 2459-2470(2002). , 1-6(2001). , 271-278(1992). , 368-373(1995). 264 ., , , 108 , 46-56(1969). 96 17 2 , G886-G894(1993). , α , 307-312(1989). , 285-293(2000). 302 , 25-30(2001). ., ., , 797-802(2003). 1 49 17A , 19-27(1976). , 939-943(1993). P 7265 P 6113 P 6740 P 6615 O 2264 M 6807 M 6932 L 6538 L 1292 L 1167 L 9539 P 1791 G 5044 F 2427 F 4176 , 467-470(1987). 69 , 187-194(2003). Prostaglandin A Piriprost potassiumsalt F 17-Phenyl-tri-norprostaglandin 17-Phenyl-tri-norprostaglandin D ONO-1301 (SC-29333) Misoprostol methylester Misoprostol feeacid Limaprost Latanoprost acid Latanoprost L-655,240 Anti-6-Ketoprostaglandin F GR 32191B Fluprostenol isopropyl ester (+)-Fluprostenol 2 α ethyl amide (continued) Strathclyde inScotland. Department ofPhysiologyandPharmacologyattheUniversity University, Professorship hewillsoontakeupaVisiting inthe prostanoid receptors. Havingjustretired from theChinese where hecontinuedhisstudiesonthecharacterizationof Chair ofPharmacologyattheChineseUniversityHongKong, nists. Hewaspromoted toReaderin1979.In1991hetookupthe tosynthesizeandtestsomeofthefirstTPreceptor antago- Wilson the prostaglandins CandD,before collaboratingwithNorman of EricHorton’s prostaglandin team,heinvestigatedtheactivitiesof Pharmacology attheUniversityofEdinburghasaLecturer. Aspart London Universityin1970.HethenjoinedtheDepartmentof Robert Jones About theAuthor 0 Raychowdhury, M.K.,etal., 80. Benoit,P., etal., 79. 3 Jones,R.L.,etal., 83. Coleman,R.A.,etal., 82. Vezza, R., 81. Chow, K.B.,etal., 78. Seiler, S.M.,etal., 77. Seiler, S,etal., 75. 4 Armstrong,R.A.,etal., 74. Schneider, J.,etal., 73. Sturzebecher, S.etal., 72. Skuballa,W., Vorbruggen, H., 71. Whittle,B.J.,etal., 70. 6 Hamanaka,N.,etal., 76. 4 Jones,R.L.,etal., 54. 7 Jones,R.L.,Chan,K.M., 57. Coleman,R.A.,etal., 56. 9 Chang,C.S.,etal., 69. 5 Gallant,M.,etal., 55. 8 Brittain,R.T., etal., 58. 8 Griffin, B.W., etal., 68. 1 Wilson,R.J., 61. Kabashima,K.,etal., 60. 9 Machwate,M.,etal., 59. 7 Woodward, D.F., etal., 67. 2 Crossley, N.S., 62. 6 Maxey, K.M.,etal., 66. Whitson,J.T., 65. Welburn, P.J., Jones,R.L., 64. 3 Jones,R.L.,Marr, C.G., 63. 1 Thromb. Haemostasis, 1 α Br. J.Pharmacol. received hisPh.D.from theSchoolofPharmacy, Expert Opin.Pharmacother. Prostaglandins J. Pharmacol.Exp.Ther. 2 Expert Opin.Ther. Patents Br. J.Pharmacol. Br. J.Pharmacol. Br. J.Pharmacol. Prostaglandins Bioorg. Med.Chem.Lett. Prostaglandins Prostaglandins Cardiovasc. DrugRev. Circulation Surv. Ophthalmol. J. Pharmacol.Exp.Ther., Br. J.Pharmacol. Prostaglandins Bioorg. Med.Chem.Lett. J. Clin.Invest. Mol. Pharmacol Br. J.Pharmacol. Prostaglandins T 0516 T 4949 S 8692 S 3065 P 9807 P 6188 P 6492 P 6738 P 0314 P 0424 P 5765 P 5640 P 5515 P 5172 P 5390 P 5265 P 4547 J. Pharmacol.Exp.Ther. Br. J.Pharmacol., Br. J.Pharmacol. Prostaglandins , , J. Biol.Chem. 10 138 Adv. Prost.Thromb.Leukot.Res. , 72 , 5-18(1975). 87 , , , 84P(2003). 53 , , , , 1208-1218(1985). 53 , , 114-121(2002). Thromboxane B Taprostene sodium Sulprostone SC 19220 Prostaglandin J Prostaglandin I Prostaglandin H Prostaglandin F Prostaglandin F Prostaglandin F Prostaglandin F Prostaglandin E Prostaglandin E Prostaglandin D Prostaglandin B Prostaglandin B Prostaglandin A 19 76 125 , 134 , , 21-35(1997). 109 , 83-90(1997). , 47 ., , , 605-627(1980). , 423-438(1982). , , 31 47 , 1288-1296(1998). , 73 225 60 , 1375-1384(2001). , 151-168(1994). , , , 61 , 883-893(2002). , , 95-109(1986). 87 , S34-S40(2002). 15 134 3 , 773-778(1981). , 36-41(2001). , , 4 , 965-977(2002). , 694-696(1977). , 1021-1026(1990). 269 12 , , 479-500(1993). , 543-551(1986). , 287-296(1978). 290 12 , 313-324(2001). , 1-11(2002). , , , 19256-19261(2002). , 2583-2586(2002). 5 , 1278-1284(1999). 305 , 1065-1070(1985). , 772-785(2003). 2 2 2 2 2 1 2 1 2 1 α 2 1 2 2 α α α sodium ethanolamide methyl ester tris , 11 , 229-305(1983).