Table Of Content4
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
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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.
Germany
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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
