4 Topics in Medicinal Chemistry EditorialBoard: P.R.Bernstein·A.Buschauer·G.J.Georg·J.A.Lowe·H.U.Stilz Transporters as Targets for Drugs Volume Editors: Susan Napier · Matilda Bingham Withcontributionsby M.D.Andrews·G.Antoni·M.Bingham·R.J.Bridges A.D.Brown·Z.Chen·S.G.Dahl·P.V.Fish·R.Gilfillan H.Hall·J.L.Katz·J.Kerr·S.Napier·A.HauckNewman S.A.Patel·A.W.Ravna·G.Sager·P.Skolnick·J.Sörensen A.Stobie·I.Sylte·F.Wakenhut·G.Walker·G.A.Whitlock G.Wishart·J.Yang 123 Drugresearchrequiresinterdisciplinaryteam-workattheinterfacebetweenchemistry,biologyand medicine.Therefore,thenewtopic-relatedseriesshouldcoverallrelevantaspectsofdrugresearch, e.g.pathobiochemistryofdiseases,identificationandvalidationof(emerging)drugtargets,structural biology,drugabilityoftargets,drugdesignapproaches,chemogenomics,syntheticchemistryinclud- ingcombinatorialmethods,bioorganicchemistry,naturalcompounds,high-throughputscreening, pharmacologicalinvitroandinvivoinvestigations,drug-receptorinteractionsonthemolecularlevel, structure-activityrelationships,drugabsorption,distribution, metabolism,elimination, toxicology andpharmacogenomics. InreferencesTopicsinMedicinalChemistryisabbreviatedTopMedChemandiscitedasajournal. SpringerWWWhomepage:springer.com VisittheTIMCcontentatspringerlink.com ISSN1862-2461 e-ISSN1862-247X ISBN978-3-540-87911-4 e-ISBN978-3-540-87912-1 DOI10.1007/978-3-540-87912-1 SpringerDordrechtHeidelbergLondonNewYork LibraryofCongressControlNumber:2009926137 (cid:1)c Springer-VerlagBerlinHeidelberg2009 Thisworkissubjecttocopyright.Allrightsarereserved,whetherthewholeorpartofthematerial isconcerned,specificallytherightsoftranslation,reprinting,reuseofillustrations,recitation,broad- casting,reproductiononmicrofilmorinanyotherway,andstorageindatabanks.Duplicationof thispublicationorpartsthereofispermittedonlyundertheprovisionsoftheGermanCopyrightLaw ofSeptember9,1965,initscurrentversion,andpermissionforusemustalwaysbeobtainedfrom Springer.ViolationsareliabletoprosecutionundertheGermanCopyrightLaw. 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Coverdesign:WMXDesignGmbH,Heidelberg TypesettingandProduction:le-texpublishingservicesoHG,Leipzig Printedonacid-freepaper SpringerispartofSpringerScience+BusinessMedia(www.springer.com) VolumeEditors Dr.SusanNapier Dr.MatildaBingham ScheringPloughCorporation ScheringPloughCorporation Newhouse, Newhouse, Motherwell,ML15SH Motherwell,ML15SH UnitedKingdom UnitedKingdom [email protected] [email protected] EditorialBoard Dr.PeterR.Bernstein Prof.Dr.GundaJ.Georg AstraZenecaPharmaceuticals UniversityofMinnesota 1800ConcordPike DepartmentofMedicalChemistry FairfaxResearchCenterB313 8-101AWeaverDensfordHall POBox15437 Minneapolis,MN55455 Wilmington,DE19850-5437 USA USA JohnA.Lowe Prof.Dr.ArminBuschauer [email protected] InstituteofPharmacy UniversityofRegensburg Universitätsstr.31 Dr.HansUlrichStilz 93053Regensburg Germany AventisPharmaDeutschlandGmbH Geb.G838 65926Frankfurta.M. 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PrefacetotheSeries Medicinalchemistryisbothscienceandart.Thescienceofmedicinalchemistry offersmankindoneofitsbesthopesforimprovingthequalityoflife.Theart ofmedicinalchemistrycontinuestochallengeitspractitionerswiththeneed for both intuition and experience to discover new drugs. Hence sharing the experience of drug discovery is uniquely beneficial to the field of medicinal chemistry. The series Topics in Medicinal Chemistry is designed to help both novice and experienced medicinal chemists share insights fromthe drug discovery process. For the novice, the introductory chapter to each volume provides background and valuable perspective on a field of medicinal chemistry not availableelsewhere.Succeeding chaptersthenprovideexamplesofsuccessful drugdiscoveryeffortsthatdescribethemostup-to-dateworkfromthisfield. Theeditorshavechosentopicsfrombothimportanttherapeuticareasand from work that advances the discipline of medicinal chemistry. For exam- ple, cancer, metabolic syndrome and Alzheimer’s disease are fields in which academiaandindustryareheavilyinvestedtodiscovernewdrugsbecauseof theirconsiderableunmetmedicalneed.Theeditorshavethereforeprioritized coveringnewdevelopmentsinmedicinalchemistryinthesefields.Inaddition, importantadvancesinthediscipline,suchasfragment-baseddrugdesignand otheraspectsofnewlead-seeking approaches,arealsoplannedforearlyvol- umesinthisseries.Eachvolumethusoffersauniqueopportunitytocapture themostup-to-dateperspectiveinanareaofmedicinalchemistry. Dr.PeterR.Bernstein Prof.Dr.ArminBuschauer Prof.Dr.GundaJ.Georg Dr.JohnLowe Dr.HansUlrichStilz PrefacetoVolume4 Transportersareproteinswhichspantheplasmamembraneandregulatethe trafficofsmallmoleculesinandoutofthecell.Transportersplayaparticularly important role in chemical signalling between neurons in the CNS, where they act to control the concentration of neurotransmitters in the synapse. The majority of transporters which are actively being pursued as targetsfor drugdiscoveryareCNSlocatedandthisreflectsthehistoryofthefieldwhich began withthetricyclic antidepressants (TCAs) over half acentury ago.The use of transporter inhibition to regulate the synaptic concentrations of key neurotransmitters is an established approach in the discovery of psychiatric medications. This volume reviews advances in the field of transporters as targetsfordrugdiscoveryinthelast10years.Thevolumewillbeofinterestto scientistsengagedindrugresearchinthepharmaceuticalindustry,biotechand academia. Followingan overview chapter, seven chapters written by leading expertsintheirareareflectarangeoftopicspertinenttothetransporterfield. Generaltopicsincluderecentadvancesinthestructuralbiologyoftransporters and its impact on potential structure-based drug design and the design of ligandsforPositronEmissionTomographyandtheimportanceofmolecular imaginginunderstandingearlyclinicaldata.Medicinalchemistryapproaches aredescribedoutliningthediscoveryofselectiveserotonin,noradrenalineand dopaminereuptakeinhibitors,currenteffortstowardsthediscoveryofmixed re-uptakeinhibitorswithvaried“flavours”ofmonoamineinhibition,advances inthedevelopmentofinhibitorsfortheglycinetransporterandthediscovery ofsubtypeselectiveEAATinhibitors.Inadditiontobeinganinterestingread, the reader will receive a critical overview of progress made in this rapidly developingfield. January2009 MatildaBingham SusanNapier Contents Overview:TransportersasTargetsforDrugDiscovery M.Bingham·S.Napier . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 MembraneTransporters:Structure,Function andTargetsforDrugDesign A.W.Ravna·G.Sager·S.G.Dahl·I.Sylte . . . . . . . . . . . . . . . . 15 DesignofMonoamineReuptakeInhibitors:SSRIs,SNRIsandNRIs G.A.Whitlock·M.D.Andrews·A.D.Brown·P.V.Fish A.Stobie·F.Wakenhut . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 AtypicalDopamineUptakeInhibitors thatProvideCluesAboutCocaine’sMechanism attheDopamineTransporter A.HauckNewman·J.L.Katz . . . . . . . . . . . . . . . . . . . . . . . 95 TheDesign,SynthesisandStructure–ActivityRelationship ofMixedSerotonin,NorepinephrineandDopamineUptakeInhibitors Z.Chen·J.Yang·P.Skolnick. . . . . . . . . . . . . . . . . . . . . . . . 131 MolecularImagingofTransporters withPositronEmissionTomography G.Antoni·J.Sörensen·H.Hall . . . . . . . . . . . . . . . . . . . . . . 155 PharmacologyofGlutamateTransportintheCNS: SubstratesandInhibitorsofExcitatoryAminoAcid Transporters(EAATs)andtheGlutamate/CystineExchangerSystemx– c R.J.Bridges·S.A.Patel . . . . . . . . . . . . . . . . . . . . . . . . . . 187 GlycineTransportersandTheirInhibitors R.Gilfillan·J.Kerr·G.Walker·G.Wishart . . . . . . . . . . . . . . . . 223 SubjectIndex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 TopMedChem(2009)4:1–13 DOI10.1007/7355_2009_029 Springer-VerlagBerlinHeidelberg Publishedonline:28March2009 Overview:TransportersasTargetsforDrugDiscovery MatildaBingham((cid:1))·SusanNapier ScheringPloughCorporation,Newhouse,MotherwellML15SH,UK [email protected] 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 2 TransporterClassification . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 2.1 TheATPBindingCassetteFamily . . . . . . . . . . . . . . . . . . . . . . . 2 2.2 TheSoluteCarrierFamily . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2.2.1 TheMajorFacilitatorSuperfamily . . . . . . . . . . . . . . . . . . . . . . . 3 2.2.2 TheNeurotransmitter:SodiumSymporterFamily . . . . . . . . . . . . . . 3 2.2.3 TheDicarboxylate/AminoAcid:Cation(Na+ orH+) Symporter(DAACS)Family . . . . . . . . . . . . . . . . . . . . . . . . . . 5 3 NSSTransporterAssays. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 4 TransportersandStructure-BasedDrugDesign(SBDD) . . . . . . . . . . 6 5 TransportersasTargetsforDrugDiscovery . . . . . . . . . . . . . . . . . 8 6 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Abbreviations ABC ATPbindingcassette ADHD Attentiondeficithyperactivitydisorder ATP Adenosinetriphosphate DAACS Dicarboxlate/aminoacid:cation(Na+ orH+)symporter DAT Dopaminereuptaketransporter EAAT Excitatoryaminoacidtransporter GLUT Glucosetransporter HTS High-throughputscreening PET Positronemissiontomography P-gp P-glycoprotein MDD Majordepressivedisorder MFS Majorfacilitatorsuperfamily NET Noradrenalinereuptaketransporter NRI Noradrenalinereuptakeinhibitor NSS Neurotransmitter;sodiumsymporter SBDD Structure-baseddrugdesign SERT Serotoninreuptaketransporter SNRI Serotoninnoradrenalineinhibitor SSRI Selectiveserotoninreuptakeinhibitor TCA Tricyclicantidepressant