review article drug repurposing is a new opportunity for...

Review ArticleDrug Repurposing Is a New Opportunity for Developing Drugsagainst Neuropsychiatric Disorders

Hyeong-Min Lee1 and Yuna Kim2

1Department of Cell Biology amp Physiology School of Medicine University of North Carolina 115 Mason Farm RoadChapel Hill NC 27599 USA2Department of Pediatrics School of Medicine Duke University 905 S LaSalle Street Durham NC 27710 USA

Correspondence should be addressed to Hyeong-Min Lee hyeong-min leemeduncedu

Received 15 December 2015 Accepted 24 February 2016

Academic Editor Luis San

Copyright copy 2016 H-M Lee and Y Kim This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Better the drugs you know than the drugs you do not know Drug repurposing is a promising fast and cost effective method thatcan overcome traditional de novo drug discovery and development challenges of targeting neuropsychiatric and other disordersDrug discovery and development targeting neuropsychiatric disorders are complicated because of the limitations in understandingpathophysiological phenomena In addition traditional de novo drug discovery and development are risky expensive and time-consuming processes One alternative approach drug repurposing has emerged taking advantage of off-target effects of theexisting drugs In order to identify new opportunities for the existing drugs it is essential for us to understand the mechanismsof action of drugs both biologically and pharmacologically By doing this drug repurposing would be a more effective method todevelop drugs against neuropsychiatric and other disorders Here we review the difficulties in drug discovery and development inneuropsychiatric disorders and the extent and perspectives of drug repurposing

1 Introduction

Theprinciple of ldquopolypharmacologyrdquo (ie one drug multiplehits or off-target effects) has been understood since theadvent of drug discovery Traditionally the goal of drugdiscovery and development was to identify the potentialtherapeutic agents using a one drug for one target modelsuggesting that high selectivity (andor affinity) would maxi-mize efficacy andminimize side effects In a series of efforts toidentify such specific compounds (like using high through-put screening) there was a problem that a vast majorityof compounds mediated unexpected and often undesiredeffects The concept of polypharmacology emerged fromthis observation (ie drug promiscuity) however polyphar-macology should be distinguished from drug promiscuityIn our definition drug promiscuity represents either goodor bad effects mediated by compounds binding to boththerapeutic and nontherapeutic targets whereas polyphar-macology represents beneficial effects mediated by com-pounds binding to multiple therapeutic targets Various drugclasses such as selective serotonin reuptake inhibitors [1 2]

antipsychotic [3] cholinesterase inhibitors [4] and throm-bolytic agents [5] show polypharmacological features Inaddition amantadine was initially developed for influenzahowever after redirection it is useful for Parkinsonrsquos disease[6 7] Zidovudinewas intended to cancer treatment and nowit is redirected to targeting HIVAIDS [8ndash10] Additionalbut well-known example is Viagra (Sildenafil) that wasintended to antianginal medication but redirected to penileerections [11] This growing evidence is against the simplicityof Ehrlichrsquos ldquomagic bullet conceptrdquo and it redirects ourattention from the one drug-multiple targetmodel tomultiplemechanisms of action Since every drug is able to hit multipletargets with and without our sense and knowledge [12]pursuing multiple targets for drugs should be accompaniedby addressing a fundamental question whether promiscuousdrugs are able to contribute to their clinical efficacy out of theoriginal scopes A direct application of polypharmacology isdrug repurposingwhich is also referred to as drug reposition-ing drug reprofiling and therapeutic switching Generallydrug repurposing refers to a reinvestigation of existing drugsfor new therapeutic interventions [13ndash17] However drug

Hindawi Publishing CorporationSchizophrenia Research and TreatmentVolume 2016 Article ID 6378137 12 pageshttpdxdoiorg10115520166378137

2 Schizophrenia Research and Treatment

repurposing does not have to narrow down to take advantageof the off-target effects of the existing drugs as discussed laterIn order to expand our knowledge and drug potentials drugrepurposing is a very productive method in drug discoveryand development It is useful for identifying and classifyingdrugs based on their actions to multiple therapeutic targets(ie leading to better efficacy andor safety) or their action tonontherapeutic targets (ie leading to adverse effects) Drugrepurposing can reduce the cost and risk intrinsic to drugdiscovery and developmentThis is especially valid regardingthe targeting of neurological and psychiatric disorders due tothe complexity in their etiology and pathology In this reviewwe will discuss the difficulties of the drug discovery andthe development process with respect to neuropsychiatricdisorders and the extent of drug repurposing as an alternativeapproach in drug discovery and development

2 Challenges in Clinical Development forNeuropsychiatric Disorders

Due to the great progress and development of modern tech-nology our understanding of biological physiological andmetabolic processes has advanced tremendously Howeverwe still face many challenges in drug discovery and develop-ment targeting neuropsychiatric disordersThere are four pri-mary reasons why it is difficult to develop therapeutic agentsagainst neuropsychiatric disorders (1) CNS disorders havea complex etiology (heterogeneity gene to environment)(2) limitations of understanding pathophysiology in neu-ropsychiatric disorders (3) lack of appropriate biomarkersandor molecular targets and (4) lack of appropriate animalmodels The etiological complexity of CNS disorders (egschizophrenia) stems frommultiple genetic and environmen-tal factors [18 19] sequentially giving rise to the other threeproblem categories mentioned above Since the etiologicalcomplexity restricts our understanding of pathophysiology ofCNS disorders it is difficult to identify andor characterizeappropriate biomarkers andor molecular targets As a resultit is difficult to evaluate the mechanism(s) of action oftherapeutic agents [20 21] In addition their pharmacologicalmanipulations targeting appropriate markers become riskyThe absence of biomarkers andor molecular targets pre-vents us from producing appropriate animal models thatare genetically manipulated to recapitulate human diseaseconditions [22] The clinical ineffectiveness of therapeuticagents may also occur due to the potential disagreementswith the biological basis in the animal models and themechanism(s) of action of therapeutic agents [23]

3 Promiscuity of Drug-Target Interactions

Due to the complex nature of neuropsychiatric disorders(eg schizophrenia depression anxiety disorders insomniamigraine headaches chronic pain and seizure disordersandor other complex mental disorders) the goal of thera-peutic intervention is daunting Although our knowledge andunderstanding of their pathophysiological phenomena havebeen greatly advanced and a series of efforts in CNS drug

discovery and development adapted cutting edge technologyof preclinical research and development the discovery of spe-cific CNS agents was not very successful and even dependedon serendipity This may be partially due to promiscuityof drug interactions Multiple aspects (eg drugs and theirtarget selectivity and affinity versus drugsrsquo molecular targetsand their mediated signaling pathways) must be consideredin clinical drug development for neuropsychiatric disor-ders Since the first introduction of the serotonin reuptakeinhibitors (SSRIs zimelidine discovered in 1971 [24 25]) andatypical antipsychotic agents (clozapine discovered in 1958[26]) the five most frequently prescribed CNS agents (olan-zapine quetiapine risperidone sertraline and venlafaxine)share commonmechanisms of action with the first two drugs(zimelidine and clozapine) Sharing mechanisms of actionimplicates that at least CNS agents may have commonmolec-ular targets or alter target-mediated signaling pathway(s) inone way or another Furthermore they may have marginaltherapeutic effects on most of the common neuropsychiatricdisorders Indeed about 70 compoundswith common targets(serotonin receptors and dopamine receptors) are underdevelopment or in current use for treating schizophreniaand about 30 drugs aim at multiple therapeutic targets inschizophrenia [27 28]This is because compounds that aimedat one target can interact with others supported by thegolden standard of clozapine that it has polypharmacologicalprofile with high affinity for several receptors as shown inFigure 1 These multiple actions of clozapine to multipletargets lead to a well-defined pharmacological signaturein schizophrenia and related disorders in agreement withpossible molecular targets in schizophrenia highlighted inTable 1 [29ndash31] However for example after several trials ofdiscovering and developing novel therapeutics like clozapinenone of the new compounds showed unique effectivenesscomparedwith clozapine [32]Thepromiscuity of drug-targetinteractions sometimes stems from a similarity therapeuticand nontherapeutic molecular targets share high homologyManymolecular targets display their sequence similarity (andthus presumably similar conformation) and drugs themselvesshow structural similarity For example therapeutic agentstargeting aminergic G-protein coupled receptors (GPCRs)are more promiscuous than other drug classes in spite ofa diversity of GPCRs [33ndash36] The similar moiety amongdrugs stems from the designated advantages over the existingdrugs that aim at knownmolecular targets andor are alreadyeffective These drug classes can obtain polypharmacologicalprofiles Defining their actions to multiple targets (therapeu-tic targets versus nontherapeutic targets) makes gaining newopportunities in CNS agent discovery in the current efforts ofclinical development for neuropsychiatric disorders difficultThus the increase in promiscuity of drug-target interactionsmakes the discovery of CNS agents more complex

4 Other Aspects in Drug-Target Interactions

We also should consider some other aspects that can provideus with the insights into the scope of CNS agent discoveryFirst two important aspects are functional selectivity and

Schizophrenia Research and Treatment 3

Arip

ipra

zole

Zipr

asid

one

Zote

pine

Risp

erid

one

Ola

nzap

ine

Cloz

apin

e

Thio

thix

ene

Loxa

pine

Hal

oper

idol

Flup

hena

zine

Chlo

rpro

maz

ine

Que

tiapi

ne

Thio

ridaz

ine

Atypicallyweight gain

Antipsychoticefficacy

Side effects

Adrenergic

Muscarinic

Weight gain

110100

100010000

Ki

5-HT1A5-HT1B5-HT1D5-HT1E5-HT2A5-HT2C

5-HT2A5-HT2C

5-HT3

5-HT5

5-HT6

5-HT7

D1

D2

D2

D3

D4

D5

1205722A1205722B1205722C1205721A1205721BM1-muscarinicM2-muscarinicM3-muscarinicM4-muscarinicM5 -muscarinic120574-A120574-BBZPNMDAPCPSERTNETDATH1

H1

H2

H3

H4

EP-3EP-4CB-1Ca2+ channelNAR a2b2NAR a2b4NAR a3b2NAR a3b4NAR ab2NAR a71205731-AR1205732-ARmGlu1mGlu2mGlu4

Figure 1 Polypharmacological profiles of antipsychotic drugs Receptoromic screening identified multiple molecular targets for severalantipsychotic drugs In particulr clozapine has the high affinity (Ki) to 5-HT serotonin receptors (5-HT2A 5-HT2C 5-HT6 and 5-HT7)dopamine receptor (D4) muscarinic receptors (M1 M2 M3 M4 and M5) adrenergic receptors (120572-1 and 120572-2) and other aminergicreceptors Other antipsychotic drugs also interact with multiple targets More information can be found at NIMH PDSP database(httppdspdbuncedupdspWebsite=kidb) (reprinted with permission from Nature Publishing Group)


Table 1 Potential molecular targets in schizophrenia

Molecular targets proposed for schizophreniaTarget family Drug actions

Dopamine receptors

D1 agonistsD2 antagonistsD4 antagonistsD4 agonists

Serotonin receptors

5-HT1A agonists5-HT1A antagonists5-HT2A antagonists5-HT4 agonists5-HT6 agonists5-HT7 agonists

Muscarinic receptorsM1 agonistsM4 agonists

M5 antagonists

GABA receptors GABAa (1205722) agonistsGABAa (1205725) antagonists

Adrenergic receptors 1205722 adrenergic antagonists

Glutamate receptors

Glycine transporter inhibitorsmGluR23 agonistsmGluR5 agonistsNMDA enhancers

Others

Nicotinic 1205727 agonistsNicotinic 12057241205732 agonists

AmpakinesCOMT inhibitors

allosterism Functional selectivity is defined as unique signal-ing pathways which are ligand-mediated The ligand can beagonist or antagonist They can modulate different signalingpathways through a single GPCR resulting in different bio-logical andor physiological processes depending on whichpathway is activated [37ndash39] Recently Allen et al studied thescaffold-based novel 120573-arrestin-biased ligand aripiprazole Astructurendashfunctionalndashselectivity relationship (SFSR) of thesenovel compounds revealed distinct 120573-arrestin-bias towardthe dopamine D2 receptor (D2R) [40] Moreover theseunique D2R 120573-arrestinndashbiased agonists displayed atypicalantipsychotic drug-like activities in vivo [41 42] Thus itis often possible that drugs which may be thought to benonselective to a particular target can actually interact withthat target However due to the complexity of phenomenainvolved in biased signaling the complete picture of theinteractions between a receptor and a ligand can be difficult toaccess [38 43 44] In addition the results from inappropriateassaysmethodologicallymay provide precarious insights intotheir functional andor molecular signatures misdirectingresearchers in the process of CNS drug discovery Howeverthe use of chimeric andor promiscuous G proteins maypartially overcome some of the potential difficulties of assess-ing drug-target interactions [45 46] although considerable

challenges remain Allosteric modulation is the positively ornegatively synergic effects on target function that are theresult of a ligand binding to the binding site (allosteric) otherthan orthosteric binding site Based on their binding effectsthese ligand molecules are categorized as being positive ofnegative allosteric modulators While the allosteric bindingsite does not accommodate endogenous ligands allostericmodulators contribute to biological and physiological pro-cesses Although the positive allosteric modulators do notactivate receptors they can enhance receptor-mediated activ-ity at the presence of endogenous ligand Since advantagesover allosteric modulation are recently recognized in drugdiscovery and development allosteric modulators appear tobe more favorable therapeutic agents [47 48] The ben-zodiazepines are well known as allosteric modulators forGABA receptors which are in clinical use However pursuingallosteric modulators cannot be a panacea in CNS agentdiscovery because the presence of an orthosteric ligand isrequired for identifying allosteric modulators This issuespecifically applies to the targeting orphan GPCRs Thereare additional problems in pursuing allosteric modulatorsAllosteric binding sites are not evolutionarily conserved[48 49] suggesting that they may be more diverse thanorthosteric binding sites Thus it is possible that newlydesigned allosteric modulators can be more selective How-ever this diversity and selectivity may cause other issuesFor example low evolutionary pressure of allosteric bindingsites may result in many differences of receptor structurebetween species which can make it difficult to employ invivo animal models The selectivity of allosteric modulatorsmay not be verified because they bind to allosteric sitesfor their own targets and they may bind to orthostericsites for nontargets Then allosteric modulator-dependentsignaling pathways could lead to adverse side effects [5051] The divergence of molecular targets also affects theefforts of CNS agent discovery Many molecular targetshave differential expression patterns andor undergo post-transcriptional andor posttranslational modifications Suchmodifications andor differential expression have significanteffects on their confirmation and functions and eventuallyalter the properties of potential molecular targets [52ndash54]It may be more difficult to identify and characterize drug-target interactions due to their divergence For examplecopy-number variations (CNVs) are recognized in risk forhuman diseases like schizophrenia [55ndash57] suggesting thatsome molecular targets among patients can be variable[58] as a result different or more promiscuous therapeuticagents are needed to aim at these variants or personalizedmedications can be an alternative solution Receptor dimer-ization or oligomerization may contribute to the divergenceof molecular targets which is another challenge for CNSagent discovery Even though the details of such mechanismsremain elusive the receptor complex that mediates differentsignaling pathways may be important in the effectiveness ofsome CNS therapeutic agents [59 60] Designed multipleligands (DMLs) which are the linked two therapeutic com-pounds may be useful for manipulating receptor functionsin targeting receptor complexes or two different receptors[60] However it may not be guaranteed whether DMLs


have polypharmacological profile Taken together due to thecomplex nature of CNS disorders and challenges in basicand clinical researches it is not surprising that we still faceobstacle to the prospect of developing novel therapeuticswith novel mechanisms To accomplish major breakthroughmajor challenges should be addressed to gain greater insightinto the complexity of CNS disorders In the next sectionwe will discuss an alternative approach (drug repurposing)in drug discovery and development in part to overcome thecurrent drug discovery issues in neuropsychiatric disorders

5 Drug Repurposing Visit Your DrugRecycling Bins

As discussed above many hurdles still exist to develop CNStherapeutic agents resulting in the fact that drug pipelineshave gradually run outThe current approaches andmethod-ology (eg high throughput screening and structure-baseddrug design)may not be an ideal solution for developingCNSagents because they are not cost and time-effective [61ndash64] Inaddition despite the extensive efforts of drug developmentseveral drugs were withdrawn from the market due to severeside effects For example thalidomide was thought to bevery safe [65] however it was withdrawn due to teratogeniceffects (although it was appreciated on the cancer therapymarket later) Thus alternative approaches are necessary forovercoming such challenges In agreement with the conceptof Sir James Black ldquothe best way to discovery a new drugis start with an existing drugrdquo [66] one of the alternativesbut a very attractive approach is drug repurposing thatis a direct application of polypharmacological features ofdrugs in drug discovery and development against neu-ropsychiatric disorders [67ndash69] Due to complex etiology ofneuropsychiatric disorders multiple therapeutic approachesmay be essential so that polypharmacological approaches arewell suited A compound hitting multiple targets may haveimproved efficacy andor safety in the view of therapeuticintervention for neuropsychiatric disorders Different levelsof polypharmacology could lead to better efficacy andorsafety or adverse effects These differences in effectivenessmay be due to the interaction of a compound with differ-ent therapeutic andor nontherapeutic targets andor dosedependence [70] As mentioned earlier polypharmacology-based drug repurposing refers to the reinvestigation of exist-ing drugs for novel therapeutic purpose [13ndash17] The existingdrugs can be currently approved drugs or even ldquofailedrdquocompounds that their original scopes have already beenidentified Failed compounds indicate abandoned drugs dueto the fact that there is no clinical effectiveness even thoughthe original scopes (eg initial targets in symptomdisorder)might be appropriate Since it is highly possible that everydrug displays off-target effects the concept of a magic bullet(one drug one target) is too simple and therefore archaicIndeed one drug can interact with diverse targets (average6ndash13 multiple targets as predicted [36]) and lead to multipleside effects It does not matter if these effects are good orbad however as those side effects allow us to see differentangles of drug usages [71ndash73] Thus polypharmacological

profiling of these drugs against any druggable targets isgreatly beneficial to drug discovery and development in orderto decrease cost and time and enhance therapeutic potentialsRepurposing can decrease the time line for drug discoveryand development From target discovery to market it takes10 to 17 years in traditional drug discovery and developmentwhereas the duration of drug discovery for repurposed drugstakes from 3 to 12 years [13] In addition known safetyand proven bioavailability of the existing drugs allow for anacceleration of the developmental process reducing failurerisk [74] although traditionally drug repurposing dependedon serendipity indicating a lack of processes and informationPresently there are a variety of innovative approaches (egcheminformatics bioinformatics and drug-target network)which may be very useful for drug repurposing Thereare several tools to recycle the existing drugs to identifynew therapeutic intervention for them as Jin and Wongsummarized [75] In order to expand therapeutic indicationof existing drugs successfully we need to be able to integratemultidisciplinary information derived from diverse fieldssuch as cheminformatics bioinformatics chemistry and invivo and in vitro pharmacological assays and clinical trialsBased on this profiling information of the drugs (eg theirknown targets toxicity safety and bioavailability) andor dis-eases of interest we can begin to find success in implementingdrug repurposing Here we will highlight several tools andmethods for drug repurposing and discuss how they cancontribute to CNS drug discovery

6 NIHM PDSP Database and Receptoromicsas Drug Repurposing Tool

As various tools and methods have been developed andrefined corresponded databases have been constructed Two-pioneered approach was dubbed receptoromics [76ndash81] andthe NIMH PDSP database (National Institute of MentalHealth Psychoactive Drug Screening Program) was created[77 82 83] Since receptoromic approach encompasses com-putational and physical screening tools it is an ideal tool fordrug repurposing In one way of a computational tool (or insilico approach) it has been referred as a receptor structure-function basis to be able to screen compounds virtually Atthe beginning several GPCR molecular models were basedon homology modeling with bovine rhodopsin [84 85]However as more validated molecular structures are solved[86ndash91] compound libraries can be screened in silico againsta virtual receptorome in order to identify potential drugand target interactions In line with in silico approach thedrug information databases are also extremely useful Suchdatabases may facilitate finding of target-specific drugs iden-tification of lead compounds and characterization of ligandrsquosstructural features The publically available database NIMHPDSP Ki was constructed from data obtained through highormedium throughput receptoromic screening this databaseis continually expanding This information provides valuableinsights into drug repurposing Another way of a physicalscreening tool has been referred to as phenotypictarget-based screening that is used for receptoromic profiling It can


(+) Fenfluramine HCl

(minus) Fenfluramine HCl

Methysergide maleate

Ergotamine tartrate

Phentemine

Fluoxetine

Norfluoxetine

(+) Norfenfluramine

(minus) Norfenfluramine

101

10100100010000

Ki (nm)

EP-3

EP-1

Aden

osin

e A2

Aden

osin

e A1

1205721B

1205721A

1205732

1205731

1205722C

1205722B

1205722A AM

PAPC

PN

MD

AH2

H1

Oxy

toci

nV3

V2

V1

BZP

GA

BAB

GA

BAA

DAT

SERT

M5

M4

M3

M4

M1

Kapp

aD

elta

MU

D5

D4

D3

D2

D1

5-H

T 75

-HT 6

5-H

T 55

-HT 2

C5

-HT 2

B5

-HT 2

A5

-HT 1

E5

-HT 1

D5

-HT 1

B5

-HT 1

A

(plusmn) Fenfluramine HCl

(plusmn) Norfenfluramine

Figure 2 The molecular targets for cardiopulmonary-associated drugs Recetoromic screening revealed the molecular targets implicated infenfluramine 5-HT2B serotonin receptor was identified as a molecular target for the norfenfluramine (a metabolite of fenfluramine) methy-lergonovine (ametabolite of the valvular heart disease- and pulmonary hypertension-associated drugmethysergide) and dihydroergotamine(potentially associated with valvular heart disease and pulmonary hypertension) The drugs associated with cardio diseases also show highaffinity to 120572-2B adrenergic receptors whereas fluoxetine and the metabolite norfluoxetine do not In this heat map the affinity of the drugsis mapped by color gradient that is blue (lower affinity higher Ki) red (higher affinity lower Ki) and intermediated color (reprinted withpermission from Nature Publishing Group)

help in the identification of molecular targets for endogenousligands The data from physical screening also comes fromligand binding screening functional screening and valida-tion of molecular targets By using such computational andphysical readouts many targets can be screened in parallelIn addition we can identify possible therapeutic or adverseeffects of the existing compounds by blindly screening themagainst multiple targets in a nonbiased way As a result sig-nificant discoveries have already been reported For example5-HT2B serotonin receptors may serve as a molecular targetresponsible for fenfluramine-induced valvular heart diseaseas receptoromic screening indicated that norfenfluraminevia activating 5-HT2B serotonin receptors was a potentialagent responsible for valvular heart disease and pulmonaryhypertension (Figure 2 Fen-phen [92ndash95]) Additionally H1histamine receptors may serve as a molecular target respon-sible for weight gain in patients taking atypical antipsychotics[96] Kappa-1 opioid receptors may serve as a moleculartarget on the hallucinogenic effects of salvinorin A [97]Thus receptoromic screening of drugs can provide insightfor repurposing drugs because this nonbiased and parallelscreening allows us to discover the molecular mechanismsresponsible for and to predict drug-mediated side effects

7 Other Databases and Potential Tools forDrug Repurposing

In addition to the NIMH PDSP database other chemicaldatabases are available For example Ligand Expo [98] ZINC[99] and KEGG DRUG [100] databases integrate diverseinformation such as molecular pathways binding experi-ments and drug targets One of the large public databasesPubChem containing the results from many screens andassays [101 102] can also facilitate drug repurposing ThePubChem database includes 61 psychiatric drugs that wereassessed in a number of different bioassays resulting inthat those drugs were identified as ldquoactiverdquo in multiplebioassays These data can be a fundamental resource of drugrepurposing The European College of Neuropsychophar-macology (ECNP) also provides valuable tools (eg ECNPMedicines chest) to help clinical researchers obtain accessto pharmacological tools important for the pursuit of theirstudies (httpswwwecnpeu) Additionally Pouliot andcolleagues already used PubChem bioassay data for predict-ing adverse drug reactions (ADRs) [103] Growing availabilityof such databases enables various tools to be applied to drugrepurposing For example Keiser et al reported Similarity


Table 2 Some examples of repurposed drugs for neuropsychiatric disorders

Drugs (alphabetic order) Actionsclasses First intervention New intervention References

Amantadine Anticholinergic-like agent Influenza Parkinsonrsquos disease ADHD [6 7]Amphotericin B NSAIDlowast Antifungal Bipolar disorder [120]Arbaclofen GABA agonist Cerebral palsy Fragile X syndrome [116 121ndash123]Atomoxetine NSRIlowastlowast Parkinsonrsquos diseases ADHD [124]

Dexmecamylamine Nicotinic receptormodulator Hypertension Depression [125 126]

Galantamine Acetylcholinesteraseinhibitor Polio paralysis Alzheimerrsquos disease [127]

Mecamylamine Nicotinic receptorantagonist Hypertension ADHD

Depression[128ndash131]

Mifepristone Glucocorticoid receptortype II antagonist

Pregnancytermination

Psychotic major depression Cushingrsquossyndrome

[132ndash135]

Ropinirole D2 agonist Hypertension Parkinsonrsquos disease idiopathic restlessleg syndrome

[136ndash138]

Tamoxifen Estrogen receptor Breast tumor Bipolar disorderMania

[139]

Valsartan Angiotensin receptorblocker Hypertension Alzheimerrsquos disease [140]

lowastNSAID is nonsteroidal anti-inflammatory druglowastlowastNSRI is norepinephrine-selective reuptake inhibitor

Ensemble Approach (SEA) to categorize molecular drugtargets through the similarity of their known molecularligands [104ndash106] This similarity based drug-target inter-action database is further used for predicting novel drug-target interactions Practically out of 30 predictions theauthors confirmed 23 in experimental assays [105] Drug-target binary associationwas created to build bipartite graphsindicating the linkage between FDA approved drugs andtarget proteins [107] Side effect similarity allowed inferringif two drugs share their targets [108] Additionally in orderto predict the potential off-target effects for any given drugligand target interactionmolecular networks [109 110] werereported The comparative toxicogenomics database (CTD)was developed to provide insight into complex chemicalgene and protein interaction [111] Adverse reactions of drugshave been mapped by bioinformatic mining of approveddrug information Based on 7684 approved drug labels theymapped the adverse reactions corresponding to 988 uniquedrugs onto 174 side effects [112 113] Weighted networkbased inference methods enable us to predict chemical andprotein interactions [114] Recently a self-organizing mapbased prediction of drug equivalence relationships (SPiDER)was developed to identify targets both for known drugsand computer-generated molecular scaffolds [115] Genome-based drug reposition is additional strength regarding thepotential tools for drug repurposing [15 116] The integrativegenome-wide metrics can provide insightful scalar theoriesof massive biological information These drug repurposingtools and multiple databases can be applied to identify newtherapeutic interventions for the existing drugs and canaccelerate CNS drug discovery

8 Conclusions

Despite the exponential growth of advanced technologyand the resultant molecular database we still do not fullyunderstand the signaling pathways and molecular mecha-nisms behind many disease states especially neuropsychi-atric disorders This lack of knowledge makes repurposingdrugs difficult and that is a direct application of polyphar-macology Drug repurposing does not eliminate the riskof compound development however it reduces the riskof the lack of compound development There are alreadyseveral CNS therapeutic drugs which have been repurposed(summarized in Table 2) Moreover another application ofpolypharmacology could be designed for multitarget ligands[67 117] If we designed ligands against profiles of multipletherapeutic targets it would accelerate CNS drug discoveryand enhance drug repurposing [60] Indeed Apsel andcoworkers reported compounds that inhibit both tyrosinekinases and phosphatidylinositol-3-OH kinases [118] Thiswork is a successful example of rational design of multitargetligands in the human kinome context In addition Besnard etal successfully launched a new approach for the automateddesign of ligands with polypharmacological profiles [119]Although it will be a challenge to rationally designmultitargetligands with therapeutic benefits advancing the automateddesign of ligands and other areas in developing optimizingand validating target combinations will be the key in thefuture for rational design of drugs with polypharmacologicalprofiles The potential advantages in computer-aided drugrepurposing enable us to prioritize CNS drug discoveryIn addition experimental approaches such as phenotypic


screening are investigated for drug repurposing [52] There-fore the application of these combinatorial approaches toneuropsychiatric disorders will not only provide great oppor-tunities in drug discovery and development but also lead tothe identification of nontherapeutic targets that can causeadverse effects

Abbreviations5-HT1A 5-Hydroxytryptamine (serotonin)

receptorsD2 Dopamine receptors1205722AR 120572 Adrenergic receptors1205732-AR 120573-Adrenergic receptorsM1 Muscarinic receptors120574-A B 120574-Aminobutyric acid receptorsBZP BenzodiazepinesNMDAR N-Methyl-D-aspartate receptorAMPAR 120572-Amino-3-hydroxy-5-methyl-4-

isoxazolepropionic acidreceptor

PCP PhencyclidineSERT Serotonin transporterNET Norepinephrine transporterDAT Dopamine transporterH1R Histamine receptorsEP-3 4 Prostaglandin receptorsCB-1 Cannabinoid receptorsNAR Nicotinic acetylcholine receptorsmGluR Metabotropic glutamate receptorsV1 Vasopressin receptors120581 120575 120583 Opioid receptors (kappa delta and mu)

Disclosure

As we focused on drug repurposing for CNS drug discoverywe may miss other valuable studies for drug repurposing

Competing Interests

Theauthors confirm that this paper content has no competinginterests

Acknowledgments

This work was supported by the Brain amp Behavior ResearchFoundation (BBRFNARSAD) Young Investigator Award(Grant no 22587) The authors would like to thank to NoahSciaky PhD at Department of Pharmacology University ofNorth Carolina Chapel Hill for proofreading

References

[1] M T Bianchi ldquoNon-serotonin anti-depressant actions direction channel modulation by SSRIs and the concept of singleagent poly-pharmacyrdquo Medical Hypotheses vol 70 no 5 pp951ndash956 2008

[2] G Rammes and R Rupprecht ldquoModulation of ligand-gatedion channels by antidepressants and antipsychoticsrdquoMolecularNeurobiology vol 35 no 2 pp 160ndash174 2007

[3] M T Bianchi ldquoPromiscuous modulation of ion channelsby anti-psychotic and anti-dementia medicationsrdquo MedicalHypotheses vol 74 no 2 pp 297ndash300 2010

[4] H Y Zhang and X C Tang ldquoNeuroprotective effects ofhuperzine A new therapeutic targets for neurodegenerativediseaserdquo Trends in Pharmacological Sciences vol 27 no 12 pp619ndash625 2006

[5] E E Benarroch ldquoTissue plasminogen activator beyond throm-bolysisrdquo Neurology vol 69 no 8 pp 799ndash802 2007

[6] N Crosby K H Deane and C E Clarke ldquoAmantadine inParkinsonrsquos diseaserdquo Cochrane Database of Systematic Reviewsno 1 Article ID CD003468 2003

[7] R S Schwab A C England Jr D C Poskanzer and R RYoung ldquoAmantadine in the treatment of Parkinsonrsquos diseaserdquoThe Journal of the American Medical Association vol 208 no7 pp 1168ndash1170 1969

[8] H Mitsuya K J Weinhold P A Furman et al ldquo31015840-Azido-31015840-deoxythymidine (BW A509U) an antiviral agent that inhibitsthe infectivity and cytopathic effect of human T-lymphotropicvirus type IIIlymphadenopathy-associated virus in vitrordquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 82 no 20 pp 7096ndash7100 1985

[9] R Sun S Eriksson and LWang ldquoIdentification and character-ization of mitochondrial factors modulating thymidine kinase2 activityrdquo Nucleosides Nucleotides amp Nucleic Acids vol 29 no4ndash6 pp 382ndash385 2010

[10] R Yarchoan R W Klecker K J Weinhold et al ldquoAdminis-tration of 31015840-azido-31015840-deoxythymidine an inhibitor of HTLV-IIILAV replication to patients with AIDS or AIDS-relatedcomplexrdquoThe Lancet vol 1 no 8481 pp 575ndash580 1986

[11] R F DeBusk C J Pepine D B Glasser A Shpilsky HDeRiesthal and M Sweeney ldquoEfficacy and safety of sildenafilcitrate in men with erectile dysfunction and stable coronaryartery diseaserdquoThe American Journal of Cardiology vol 93 no2 pp 147ndash153 2004

[12] W K Kroeze and B L Roth ldquoPolypharmacological drugsldquomagic shotgunsrdquo for psychiatric diseasesrdquo inPolypharmacologyin Drug Discovery J-U Peters Ed pp 135ndash148 John Wiley ampSons Somerset NJ USA 2012

[13] T T Ashburn and K B Thor ldquoDrug repositioning identifyingand developing new uses for existing drugsrdquo Nature ReviewsDrug Discovery vol 3 no 8 pp 673ndash683 2004

[14] A L Hopkins ldquoDrug discovery predicting promiscuityrdquoNature vol 462 no 7270 pp 167ndash168 2009

[15] K Marusina D J Welsch L Rose D Brock and N BahrldquoThe CTSA Pharmaceutical Assets Portalmdasha public-privatepartnership model for drug repositioningrdquo Drug DiscoveryToday Therapeutic Strategies vol 8 no 3-4 pp 77ndash83 2011

[16] K A OrsquoConnor and B L Roth ldquoFinding new tricks for olddrugs an efficient route for public-sector drug discoveryrdquoNature Reviews Drug Discovery vol 4 no 12 pp 1005ndash10142005

[17] T I Oprea J E Bauman C G Bologa et al ldquoDrug repurposingfrom an academic perspectiverdquo Drug Discovery Today Thera-peutic Strategies vol 8 no 3-4 pp 61ndash69 2011

[18] P J Harrison andM J Owen ldquoGenes for schizophrenia Recentfindings and their pathophysiological implicationsrdquoThe Lancetvol 361 no 9355 pp 417ndash419 2003

[19] C M Lewis D F Levinson L H Wise et al ldquoGenome scanmeta-analysis of schizophrenia and bipolar disorder part IIschizophreniardquo American Journal of Human Genetics vol 73no 1 pp 34ndash48 2003


[20] J T Coyle and R S Duman ldquoFinding the intracellular signalingpathways affected by mood disorder treatmentsrdquo Neuron vol38 no 2 pp 157ndash160 2003

[21] B L Roth D Sheffler and S G Potkin ldquoAtypical antipsychoticdrug actions unitary or multiple mechanisms for lsquoatypicalityrsquordquoClinical Neuroscience Research vol 3 no 1-2 pp 108ndash117 2003

[22] V Setola and B L Roth ldquoWhy mice are neither minia-ture humans nor small rats a cautionary tale involving5-hydroxytryptamine-6 serotonin receptor species variantsrdquoMolecular Pharmacology vol 64 no 6 pp 1277ndash1278 2003

[23] E Shorter ldquoLooking backwards a possible new path fordrug discovery in psychopharmacologyrdquo Nature Reviews DrugDiscovery vol 1 no 12 pp 1003ndash1006 2002

[24] A Carlsson and D T Wong ldquoA note on the discovery ofselective serotonin reuptake inhibitorsrdquo Life Sciences vol 61 no12 p 1203 1997

[25] D T Wong F P Bymaster and E A Engleman ldquoProzac(fluoxetine lilly 110140) the first selective serotonin uptakeinhibitor and an antidepressant drug twenty years since its firstpublicationrdquo Life Sciences vol 57 no 5 pp 411ndash441 1995

[26] H Hippius ldquoA historical perspective of clozapinerdquo The Journalof Clinical Psychiatry vol 60 supplement 12 pp 22ndash23 1999

[27] P J Conn and B L Roth ldquoOpportunities and challenges ofpsychiatric drug discovery roles for scientists in academicindustry and government settingsrdquo Neuropsychopharmacologyvol 33 no 9 pp 2048ndash2060 2008

[28] J A Gray and B L Roth ldquoThe pipeline and future of drugdevelopment in schizophreniardquo Molecular Psychiatry vol 12no 10 pp 904ndash922 2007

[29] J A Gray and B L Roth ldquoMolecular targets for treatingcognitive dysfunction in schizophreniardquo Schizophrenia Bulletinvol 33 no 5 pp 1100ndash1119 2007

[30] J Kane G Honigfeld J Singer and H Meltzer ldquoClozapine forthe treatment-resistant schizophrenic A double-blind compar-ison with chlorpromazinerdquo Archives of General Psychiatry vol45 no 9 pp 789ndash796 1988

[31] H Y Meltzer L Alphs A I Green et al ldquoClozapine treatmentfor suicidality in schizophrenia International Suicide Preven-tion Trial (InterSePT)rdquo Archives of General Psychiatry vol 60no 1 pp 82ndash91 2003

[32] J Brea M Castro M I Loza et al ldquoQF2004B a potentialantipsychotic butyrophenone derivative with similar pharma-cological properties to clozapinerdquo Neuropharmacology vol 51no 2 pp 251ndash262 2006

[33] A Anighoro and G Rastelli ldquoEnrichment factor analyses onG-protein coupled receptors with known crystal structurerdquoJournal of Chemical Information andModeling vol 53 no 4 pp739ndash743 2013

[34] E Gregori-Puigjane and J Mestres ldquoA ligand-based approachto mining the chemogenomic space of drugsrdquo CombinatorialChemistry amp High Throughput Screening vol 11 no 8 pp 669ndash676 2008

[35] B Selvam S L Porter and I G Tikhonova ldquoAddressingselective polypharmacology of antipsychotic drugs targetingthe bioaminergic receptors through receptor dynamic con-formational ensemblesrdquo Journal of Chemical Information andModeling vol 53 no 7 pp 1761ndash1774 2013

[36] I Vogt and J Mestres ldquoDrug-target networksrdquo MolecularInformatics vol 29 no 1-2 pp 10ndash14 2010

[37] B L Roth and D-M Chuang ldquoMultiple mechanisms ofserotonergic signal transductionrdquo Life Sciences vol 41 no 9 pp1051ndash1064 1987

[38] J D Urban W P Clarke M von Zastrow et al ldquoFunctionalselectivity and classical concepts of quantitative pharmacologyrdquoJournal of Pharmacology and Experimental Therapeutics vol320 no 1 pp 1ndash13 2007

[39] J D Urban G A Vargas M von Zastrow and R B MailmanldquoAripiprazole has functionally selective actions at dopamineD2receptor-mediated signaling pathwaysrdquo Neuropsychophar-

macology vol 32 no 1 pp 67ndash77 2007[40] J Jin B L Roth and S Frye ldquoNovel Functionally Selective

Ligands of Dopamine D2 Receptorsrdquo US Patent 201301376792013

[41] J A Allen J M Yost V Setola et al ldquoDiscovery of 120573-arrestin-biased dopamine D2 ligands for probing signal transductionpathways essential for antipsychotic efficacyrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 108 no 45 pp 18488ndash18493 2011

[42] X Chen M F Sassano L Zheng et al ldquoStructure-functionalselectivity relationship studies of 120573-arrestin-biased dopamineD2receptor agonistsrdquo Journal of Medicinal Chemistry vol 55

no 16 pp 7141ndash7153 2012[43] J A Allen and B L Roth ldquoStrategies to discover unexpected

targets for drugs active at G protein-coupled receptorsrdquo AnnualReview of Pharmacology and Toxicology vol 51 pp 117ndash1442011

[44] R B Mailman ldquoGPCR functional selectivity has therapeuticimpactrdquo Trends in Pharmacological Sciences vol 28 no 8 pp390ndash396 2007

[45] P Coward S D Chan H G Wada G M Humphries and BR Conklin ldquoChimeric G proteins allow a high-throughput sig-naling assay of Gi-coupled receptorsrdquo Analytical Biochemistryvol 270 no 2 pp 242ndash248 1999

[46] E Kostenis M Waelbroeck and G Milligan ldquoTechniquespromiscuous G120572 proteins in basic research and drug discoveryrdquoTrends in Pharmacological Sciences vol 26 no 11 pp 595ndash6022005

[47] T P Kenakin ldquoLigand detection in the allosteric worldrdquo Journalof Biomolecular Screening vol 15 no 2 pp 119ndash130 2010

[48] L T May K Leach P M Sexton and A ChristopoulosldquoAllosteric modulation of G protein-coupled receptorsrdquoAnnualReview of Pharmacology and Toxicology vol 47 pp 1ndash51 2007

[49] J A Lewis E P Lebois and C W Lindsley ldquoAllosteric modu-lation of kinases and GPCRs design principles and structuraldiversityrdquo Current Opinion in Chemical Biology vol 12 no 3pp 269ndash280 2008

[50] Z Fang C Grutter and D Rauh ldquoStrategies for the selectiveregulation of kinases with allosteric modulators exploitingexclusive structural featuresrdquo ACS Chemical Biology vol 8 no1 pp 58ndash70 2013

[51] B J Melancon C R Hopkins M R Wood et al ldquoAllostericmodulation of seven transmembrane spanning receptors the-ory practice and opportunities for central nervous system drugdiscoveryrdquo Journal of Medicinal Chemistry vol 55 no 4 pp1445ndash1464 2012

[52] A Anighoro J Bajorath and G Rastelli ldquoPolypharmacologychallenges and opportunities in drug discoveryrdquo Journal ofMedicinal Chemistry vol 57 no 19 pp 7874ndash7887 2014

[53] T Arya C Kishor V Saddanapu R Reddi and A AddlagattaldquoDiscovery of a new genetic variant of methionine aminopep-tidase from Streptococci with possible post-translational mod-ifications biochemical and structural characterizationrdquo PLoSONE vol 8 no 10 Article ID e75207 2013


[54] R Nistico C Ferraina V Marconi et al ldquoAge-related changesof protein SUMOylation balance in the A120573PP Tg2576 mousemodel of Alzheimerrsquos diseaserdquo Frontiers in Pharmacology vol5 article 63 2014

[55] A S Bassett S W Scherer and L M Brzustowicz ldquoCopynumber variations in schizophrenia critical review and newperspectives on concepts of genetics and diseaserdquoTheAmericanJournal of Psychiatry vol 167 no 8 pp 899ndash914 2010

[56] H M Grayton C Fernandes D Rujescu and D A CollierldquoCopy number variations in neurodevelopmental disordersrdquoProgress in Neurobiology vol 99 no 1 pp 81ndash91 2012

[57] CNHenrichsen E Chaignat andAReymond ldquoCopynumbervariants diseases and gene expressionrdquo Human MolecularGenetics vol 18 no 1 pp R1ndashR8 2009

[58] E H Cook Jr and S W Scherer ldquoCopy-number variationsassociated with neuropsychiatric conditionsrdquo Nature vol 455no 7215 pp 919ndash923 2008

[59] Z Liu J Zhang and A Zhang ldquoDesign of multivalent ligandtargeting G-protein-coupled receptorsrdquo Current Pharmaceuti-cal Design vol 15 no 6 pp 682ndash718 2009

[60] R Morphy and Z Rankovic ldquoDesigned multiple ligandsAn emerging drug discovery paradigmrdquo Journal of MedicinalChemistry vol 48 no 21 pp 6523ndash6543 2005

[61] C P Adams andVV Brantner ldquoEstimating the cost of newdrugdevelopment is it really 802million dollarsrdquoHealth Affairs vol25 no 2 pp 420ndash428 2006

[62] I M Kapetanovic ldquoComputer-aided drug discovery and devel-opment (CADDD) in silico-chemico-biological approachrdquoChemico-Biological Interactions vol 171 no 2 pp 165ndash1762008

[63] M Pirmohamed S James S Meakin et al ldquoAdverse drugreactions as cause of admission to hospital prospective analysisof 18 820 patientsrdquoBritishMedical Journal vol 329 no 7456 pp15ndash19 2004

[64] R Shankar X Frapaise and B Brown ldquoLEAN drug develop-ment in RampDrdquoDrug Discovery amp Development vol 9 no 5 pp57ndash60 2006

[65] A Rowan Of Mice Models and Men A Critical Evaluation ofAnimal Research State University of New York Press AlbanyNY USA 1984

[66] T N Raju ldquoThe Nobel chronicles 1988 James Whyte Black(b 1924) Gertrude Elion (1918ndash99) and George H Hitchings(1905ndash98)rdquoThe Lancet vol 355 no 9208 p 1022 2000

[67] A L Hopkins J S Mason and J P Overington ldquoCan werationally design promiscuous drugsrdquo Current Opinion inStructural Biology vol 16 no 1 pp 127ndash136 2006

[68] I Nobeli A D Favia and J MThornton ldquoProtein promiscuityand its implications for biotechnologyrdquo Nature Biotechnologyvol 27 no 2 pp 157ndash167 2009

[69] J-U Peters P Schnider P Mattei and M Kansy ldquoPharma-cological promiscuity dependence on compound propertiesand target specificity in a set of recent Roche compoundsrdquoChemMedChem vol 4 no 4 pp 680ndash686 2009

[70] A Merino A K Bronowska D B Jackson and D J CahillldquoDrug profiling knowing where it hitsrdquo Drug Discovery Todayvol 15 no 17-18 pp 749ndash756 2010

[71] A S Reddy and S Zhang ldquoPolypharmacology drug discoveryfor the futurerdquo Expert Review of Clinical Pharmacology vol 6no 1 pp 41ndash47 2013

[72] Z Simon A Peragovics M Vigh-Smeller et al ldquoDrug effectprediction by polypharmacology-based interaction profilingrdquo

Journal of Chemical Information andModeling vol 52 no 1 pp134ndash145 2012

[73] M A Yildirim K-I Goh M E Cusick A-L Barabasi and MVidal ldquoDrug-target networkrdquoNature Biotechnology vol 25 no10 pp 1119ndash1126 2007

[74] B M Padhy and Y K Gupta ldquoDrug repositioning re-investigating existing drugs for new therapeutic indicationsrdquoJournal of PostgraduateMedicine vol 57 no 2 pp 153ndash160 2011

[75] G Jin and S T C Wong ldquoToward better drug repositioningprioritizing and integrating existing methods into efficientpipelinesrdquo Drug Discovery Today vol 19 no 5 pp 637ndash6442014

[76] B N Armbruster and B L Roth ldquoMining the receptoromerdquoTheJournal of Biological Chemistry vol 280 no 7 pp 5129ndash51322005

[77] N H Jensen and B L Roth ldquoMassively parallel screening ofthe receptoromerdquo Combinatorial Chemistry amp HighThroughputScreening vol 11 no 6 pp 420ndash426 2008

[78] B L Roth ldquoReceptor systems will mining the receptoromeyield novel targets for pharmacotherapyrdquo Pharmacology ampTherapeutics vol 108 no 1 pp 59ndash64 2005

[79] B L Roth and W K Kroeze ldquoScreening the receptoromeyields validated molecular targets for drug discoveryrdquo CurrentPharmaceutical Design vol 12 no 14 pp 1785ndash1795 2006

[80] B L Roth D J Sheffer and W K Kroeze ldquoMagic shotgunsversus magic bullets selectively non-selective drugs for mooddisorders and schizophreniardquo Nature Reviews Drug Discoveryvol 3 no 4 pp 353ndash359 2004

[81] R T Strachan G Ferrara and B L Roth ldquoScreening thereceptorome an efficient approach for drug discovery andtarget validationrdquo Drug Discovery Today vol 11 no 15-16 pp708ndash716 2006

[82] B L Roth E Lopez S Beischel R B Westkaemper and J MEvans ldquoScreening the receptorome to discover the moleculartargets for plant-derived psychoactive compounds a novelapproach for CNS drug discoveryrdquo Pharmacology amp Therapeu-tics vol 102 no 2 pp 99ndash110 2004

[83] B L Roth E Lopez S Patel and W K Kroeze ldquoThe multi-plicity of serotonin receptors uselessly diverse molecules or anembarrassment of richesrdquoNeuroscientist vol 6 no 4 pp 252ndash262 2000

[84] J A Ballesteros L Shi and J A Javitch ldquoStructural mimicryin G protein-coupled receptors Implications of the high-resolution structure of rhodopsin for structure-function anal-ysis of rhodopsin-like receptorsrdquoMolecular Pharmacology vol60 no 1 pp 1ndash19 2001

[85] D A Shapiro K Kristiansen D M Weiner W K Kroeze andB L Roth ldquoEvidence for a model of agonist-induced activationof 5-hydroxytryptamine 2A serotonin receptors that involvesthe disruption of a strong ionic interaction between helices 3and 6rdquo Journal of Biological Chemistry vol 277 no 13 pp 11441ndash11449 2002

[86] G Fenalti P M Giguere V Katritch et al ldquoMolecular controlof 120575-opioid receptor signallingrdquo Nature vol 506 no 7487 pp191ndash196 2014

[87] E Vardy P D Mosier K J Frankowski et al ldquoChemotype-selective modes of action of 120581-opioid receptor agonistsrdquo TheJournal of Biological Chemistry vol 288 no 48 pp 34470ndash34483 2013

[88] C Wang Y Jiang J Ma et al ldquoStructural basis for molecularrecognition at serotonin receptorsrdquo Science vol 340 no 6132pp 610ndash614 2013


[89] C Wang H Wu T Evron et al ldquoStructural basis forSmoothened receptor modulation and chemoresistance to anti-cancer drugsrdquoNature Communications vol 5 article 4355 2014

[90] C Wang H Wu V Katritch et al ldquoStructure of the humansmoothened receptor bound to an antitumour agentrdquo Naturevol 497 no 7449 pp 338ndash343 2013

[91] H Wu D Wacker M Mileni et al ldquoStructure of the human120581-opioid receptor in complex with JDTicrdquo Nature vol 485 no7398 pp 327ndash332 2012

[92] J D Hutcheson V Setola B L Roth and W D MerrymanldquoSerotonin receptors and heart valve diseasemdashit was meant 2BrdquoPharmacology ampTherapeutics vol 132 no 2 pp 146ndash157 2011

[93] R B Rothman M H Baumann J E Savage et al ldquoEvidencefor possible involvement of 5-HT(2B) receptors in the cardiacvalvulopathy associated with fenfluramine and other seroton-ergic medicationsrdquo Circulation vol 102 no 23 pp 2836ndash28412000

[94] V Setola S J Hufeisen K J Grande-Allen et al ldquo34-Meth-ylenedioxymethamphetamine (MDMA lsquoEcstasyrsquo) induces fen-fluramine-like proliferative actions on human cardiac valvularinterstitial cells in vitrordquoMolecular Pharmacology vol 63 no 6pp 1223ndash1229 2003

[95] V Setola and B L Roth ldquoScreening the receptorome revealsmolecular targets responsible for drug-induced side effectsfocus on lsquofen-phenrsquordquo Expert Opinion on Drug Metabolism ampToxicology vol 1 no 3 pp 377ndash387 2005

[96] W K Kroeze S J Hufeisen B A Popadak et al ldquoH1-histaminereceptor affinity predicts short-term weight gain for typical andatypical antipsychotic drugsrdquo Neuropsychopharmacology vol28 no 3 pp 519ndash526 2003

[97] B L Roth K Baner R Westkaemper et al ldquoSalvinorin A apotent naturally occurring nonnitrogenous 120581 opioid selectiveagonistrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 99 no 18 pp 11934ndash11939 2002

[98] Z Feng L Chen HMaddula et al ldquoLigandDepot a data ware-house for ligands bound to macromoleculesrdquo Bioinformaticsvol 20 no 13 pp 2153ndash2155 2004

[99] J J Irwin and B K Shoichet ldquoZINCmdasha free database of com-mercially available compounds for virtual screeningrdquo Journal ofChemical Information and Modeling vol 45 no 1 pp 177ndash1822005

[100] M Kanehisa S Goto Y Sato M Furumichi and M TanabeldquoKEGG for integration and interpretation of large-scale molec-ular data setsrdquo Nucleic Acids Research vol 40 no 1 pp D109ndashD114 2012

[101] Y Wang J Xiao T O Suzek et al ldquoPubChemrsquos BioAssaydatabaserdquoNucleic Acids Research vol 40 no 1 pp D400ndashD4122012

[102] D L Wheeler T Barrett D A Benson et al ldquoDatabaseresources of the National Center for Biotechnology Informa-tionrdquo Nucleic Acids Research vol 36 no 1 pp D13ndashD21 2008

[103] Y Pouliot A PChiang andA J Butte ldquoPredicting adverse drugreactions using publicly available PubChem BioAssay datardquoClinical Pharmacology and Therapeutics vol 90 no 1 pp 90ndash99 2011

[104] M J Keiser B L Roth B N Armbruster P Ernsberger J JIrwin and B K Shoichet ldquoRelating protein pharmacology byligand chemistryrdquo Nature Biotechnology vol 25 no 2 pp 197ndash206 2007

[105] M J Keiser V Setola J J Irwin et al ldquoPredicting newmoleculartargets for known drugsrdquoNature vol 462 no 7270 pp 175ndash1812009

[106] E Lounkine M J Keiser S Whitebread et al ldquoLarge-scaleprediction and testing of drug activity on side-effect targetsrdquoNature vol 486 no 7403 pp 361ndash367 2012

[107] A-L Barabasi and Z N Oltvai ldquoNetwork biology understand-ing the cellrsquos functional organizationrdquo Nature Reviews Geneticsvol 5 no 2 pp 101ndash113 2004

[108] M Campillos M Kuhn A-C Gavin L J Jensen and P BorkldquoDrug target identification using side-effect similarityrdquo Sciencevol 321 no 5886 pp 263ndash266 2008

[109] J K Morrow L Tian and S Zhang ldquoMolecular networks indrug discoveryrdquo Critical Reviews in Biomedical Engineering vol38 no 2 pp 143ndash156 2010

[110] L Tian and S Zhang ldquoMapping drug-target interaction net-worksrdquo in Proceedings of the Annual International Conferenceof the IEEE Engineering in Medicine and Biology Society (EMBCrsquo09) pp 2336ndash2339 IEEEMinneapolisMinn USA September2009

[111] A P Davis B L King S Mockus et al ldquoThe comparativetoxicogenomics database update 2011rdquo Nucleic Acids Researchvol 39 no 1 pp D1067ndashD1072 2011

[112] T I Oprea and J Mestres ldquoDrug repurposing far beyond newtargets for old drugsrdquoThe AAPS Journal vol 14 no 4 pp 759ndash763 2012

[113] T I Oprea S Kim Nielsen O Ursu et al ldquoAssociatingdrugs targets and clinical outcomes into an integrated networkaffords a new platform for computer-aided drug repurposingrdquoMolecular Informatics vol 30 no 2-3 pp 100ndash111 2011

[114] F Cheng Y Zhou W Li G Liu and Y Tang ldquoPrediction ofchemical-protein interactions network with weighted network-based inference methodrdquo PLoS ONE vol 7 no 7 Article IDe41064 2012

[115] D Reker T Rodrigues P Schneider and G Schneider ldquoIdenti-fying themacromolecular targets of de novo-designed chemicalentities through self-organizing map consensusrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 111 no 11 pp 4067ndash4072 2014

[116] C A Erickson J M Veenstra-Vanderweele R D Melmed etal ldquoSTX209 (arbaclofen) for autism spectrum disorders an 8-week open-label studyrdquo Journal of Autism and DevelopmentalDisorders vol 44 no 4 pp 958ndash964 2014

[117] J R Morphy and C J Harris Designing Multi-Target DrugsRoyal Society of Chemistry London UK 2012

[118] B Apsel J A Blair B Gonzalez et al ldquoTargeted polypharma-cology discovery of dual inhibitors of tyrosine and phospho-inositide kinasesrdquo Nature Chemical Biology vol 4 no 11 pp691ndash699 2008

[119] J Besnard G F Ruda V Setola et al ldquoAutomated design ofligands to polypharmacological profilesrdquo Nature vol 492 no7428 pp 215ndash220 2012

[120] K D McLaren and L B Marangell ldquoSpecial considerations inthe treatment of patients with bipolar disorder and medical co-morbiditiesrdquo Annals of General Hospital Psychiatry vol 3 no 1article 7 2004

[121] E M Berry-Kravis D Hessl B Rathmell et al ldquoEffects ofSTX209 (arbaclofen) on neurobehavioral function in childrenand adults with fragile X syndrome a randomized controlledphase 2 trialrdquo Science Translational Medicine vol 4 no 152Article ID 152ra127 2012

[122] A Healy R Rush and T Ocain ldquoFragile X syndrome anupdate on developing treatment modalitiesrdquo ACS ChemicalNeuroscience vol 2 no 8 pp 402ndash410 2011


[123] R Lozano E B Hare and R J Hagerman ldquoModulation of theGABAergic pathway for the treatment of fragile X syndromerdquoNeuropsychiatric Disease and Treatment vol 10 pp 1769ndash17792014

[124] M R Mohammadi L Kashani S Akhondzadeh E S Iza-dian and S Ohadinia ldquoEfficacy of theophylline compared tomethylphenidate for the treatment of attention-deficit hyper-activity disorder in children and adolescents a pilot double-blind randomized trialrdquo Journal of Clinical Pharmacy andTherapeutics vol 29 no 2 pp 139ndash144 2004

[125] H J Moller K Demyttenaere B Olausson et al ldquoTwo phaseIII randomised double-blind studies of fixed-dose TC-5214(dexmecamylamine) adjunct to ongoing antidepressant therapyin patients with major depressive disorder and an inadequateresponse to prior antidepressant therapyrdquoTheWorld Journal ofBiological Psychiatry vol 16 no 7 pp 483ndash501 2015

[126] E VietaM EThase D Naber et al ldquoEfficacy and tolerability offlexibly-dosed adjunct TC-5214 (dexmecamylamine) in patientswith major depressive disorder and inadequate response toprior antidepressantrdquo European Neuropsychopharmacology vol24 no 4 pp 564ndash574 2014

[127] A Corbett J Smith and C Ballard ldquoNew and emergingtreatments for Alzheimers diseaserdquo Expert Review of Neurother-apeutics vol 12 no 5 pp 535ndash543 2012

[128] T P George K A Sacco J C Vessicchio A HWeinberger andR D Shytle ldquoNicotinic antagonist augmentation of selectiveserotonin reuptake inhibitor-refractory major depressive disor-der a preliminary studyrdquo Journal of Clinical Psychopharmacol-ogy vol 28 no 3 pp 340ndash344 2008

[129] E D Levin and B B Simon ldquoNicotinic acetylcholine involve-ment in cognitive function in animalsrdquo Psychopharmacologyvol 138 no 3-4 pp 217ndash230 1998

[130] A Singh D K Das and M E Kelley ldquoMecamylamineTargaceptrdquo IDrugs vol 9 no 3 pp 205ndash217 2006

[131] K-I Ueno H Togashi M Matsumoto S Ohashi H Saito andM Yoshioka ldquo12057241205732 Nicotinic acetylcholine receptor activationameliorates impairment of spontaneous alternation behaviorin stroke-prone spontaneously hypertensive rats an animalmodel of attention deficit hyperactivity disorderrdquo The Journalof Pharmacology and Experimental Therapeutics vol 302 no 1pp 95ndash100 2002

[132] J K Belanoff B H Flores M Kalezhan B Sund and AF Schatzberg ldquoRapid reversal of psychotic depression usingmifepristonerdquo Journal of Clinical Psychopharmacology vol 21no 5 pp 516ndash521 2001

[133] C M Blasey T S Block J K Belanoff and R L Roe ldquoEfficacyand safety of mifepristone for the treatment of psychoticdepressionrdquo Journal of Clinical Psychopharmacology vol 31 no4 pp 436ndash440 2011

[134] B J Carroll and R T Rubin ldquoMifepristone in psychoticdepressionrdquo Biological Psychiatry vol 63 no 1 pp e1ndashe3 2008

[135] R H Howland ldquoMifepristone as a therapeutic agent in psychia-tryrdquo Journal of Psychosocial Nursing andMental Health Servicesvol 51 no 6 pp 11ndash14 2013

[136] C E Clarke andKHDeane ldquoRopinirole for levodopa-inducedcomplications in Parkinsonrsquos diseaserdquoTheCochrane Database ofSystematic Reviews vol 3 Article ID CD001516 2000

[137] C E Clarke andKHDeane ldquoRopinirole for levodopa-inducedcomplications in Parkinsonrsquos diseaserdquoTheCochrane Database ofSystematic Reviews no 1 Article ID CD001516 2001

[138] R Tomasiuk S Szlufik A Friedman and D KoziorowskildquoRopinirole treatment in Parkinsonrsquos disease associated with

higher serum level of inflammatory biomarker NT-proCNPrdquoNeuroscience Letters vol 566 pp 147ndash150 2014

[139] A Yildiz S Guleryuz D P Ankerst D Ongur and P FRenshaw ldquoProtein kinase C inhibition in the treatment ofmania a double-blind placebo-controlled trial of tamoxifenrdquoArchives of General Psychiatry vol 65 no 3 pp 255ndash263 2008

[140] A Corbett G Williams and C Ballard ldquoDrug repositioningan opportunity to develop novel treatments for Alzheimerrsquosdiseaserdquo Pharmaceuticals vol 6 no 10 pp 1304ndash1321 2013

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


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Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


repurposing does not have to narrow down to take advantageof the off-target effects of the existing drugs as discussed laterIn order to expand our knowledge and drug potentials drugrepurposing is a very productive method in drug discoveryand development It is useful for identifying and classifyingdrugs based on their actions to multiple therapeutic targets(ie leading to better efficacy andor safety) or their action tonontherapeutic targets (ie leading to adverse effects) Drugrepurposing can reduce the cost and risk intrinsic to drugdiscovery and developmentThis is especially valid regardingthe targeting of neurological and psychiatric disorders due tothe complexity in their etiology and pathology In this reviewwe will discuss the difficulties of the drug discovery andthe development process with respect to neuropsychiatricdisorders and the extent of drug repurposing as an alternativeapproach in drug discovery and development

2 Challenges in Clinical Development forNeuropsychiatric Disorders

Due to the great progress and development of modern tech-nology our understanding of biological physiological andmetabolic processes has advanced tremendously Howeverwe still face many challenges in drug discovery and develop-ment targeting neuropsychiatric disordersThere are four pri-mary reasons why it is difficult to develop therapeutic agentsagainst neuropsychiatric disorders (1) CNS disorders havea complex etiology (heterogeneity gene to environment)(2) limitations of understanding pathophysiology in neu-ropsychiatric disorders (3) lack of appropriate biomarkersandor molecular targets and (4) lack of appropriate animalmodels The etiological complexity of CNS disorders (egschizophrenia) stems frommultiple genetic and environmen-tal factors [18 19] sequentially giving rise to the other threeproblem categories mentioned above Since the etiologicalcomplexity restricts our understanding of pathophysiology ofCNS disorders it is difficult to identify andor characterizeappropriate biomarkers andor molecular targets As a resultit is difficult to evaluate the mechanism(s) of action oftherapeutic agents [20 21] In addition their pharmacologicalmanipulations targeting appropriate markers become riskyThe absence of biomarkers andor molecular targets pre-vents us from producing appropriate animal models thatare genetically manipulated to recapitulate human diseaseconditions [22] The clinical ineffectiveness of therapeuticagents may also occur due to the potential disagreementswith the biological basis in the animal models and themechanism(s) of action of therapeutic agents [23]

3 Promiscuity of Drug-Target Interactions

Due to the complex nature of neuropsychiatric disorders(eg schizophrenia depression anxiety disorders insomniamigraine headaches chronic pain and seizure disordersandor other complex mental disorders) the goal of thera-peutic intervention is daunting Although our knowledge andunderstanding of their pathophysiological phenomena havebeen greatly advanced and a series of efforts in CNS drug

discovery and development adapted cutting edge technologyof preclinical research and development the discovery of spe-cific CNS agents was not very successful and even dependedon serendipity This may be partially due to promiscuityof drug interactions Multiple aspects (eg drugs and theirtarget selectivity and affinity versus drugsrsquo molecular targetsand their mediated signaling pathways) must be consideredin clinical drug development for neuropsychiatric disor-ders Since the first introduction of the serotonin reuptakeinhibitors (SSRIs zimelidine discovered in 1971 [24 25]) andatypical antipsychotic agents (clozapine discovered in 1958[26]) the five most frequently prescribed CNS agents (olan-zapine quetiapine risperidone sertraline and venlafaxine)share commonmechanisms of action with the first two drugs(zimelidine and clozapine) Sharing mechanisms of actionimplicates that at least CNS agents may have commonmolec-ular targets or alter target-mediated signaling pathway(s) inone way or another Furthermore they may have marginaltherapeutic effects on most of the common neuropsychiatricdisorders Indeed about 70 compoundswith common targets(serotonin receptors and dopamine receptors) are underdevelopment or in current use for treating schizophreniaand about 30 drugs aim at multiple therapeutic targets inschizophrenia [27 28]This is because compounds that aimedat one target can interact with others supported by thegolden standard of clozapine that it has polypharmacologicalprofile with high affinity for several receptors as shown inFigure 1 These multiple actions of clozapine to multipletargets lead to a well-defined pharmacological signaturein schizophrenia and related disorders in agreement withpossible molecular targets in schizophrenia highlighted inTable 1 [29ndash31] However for example after several trials ofdiscovering and developing novel therapeutics like clozapinenone of the new compounds showed unique effectivenesscomparedwith clozapine [32]Thepromiscuity of drug-targetinteractions sometimes stems from a similarity therapeuticand nontherapeutic molecular targets share high homologyManymolecular targets display their sequence similarity (andthus presumably similar conformation) and drugs themselvesshow structural similarity For example therapeutic agentstargeting aminergic G-protein coupled receptors (GPCRs)are more promiscuous than other drug classes in spite ofa diversity of GPCRs [33ndash36] The similar moiety amongdrugs stems from the designated advantages over the existingdrugs that aim at knownmolecular targets andor are alreadyeffective These drug classes can obtain polypharmacologicalprofiles Defining their actions to multiple targets (therapeu-tic targets versus nontherapeutic targets) makes gaining newopportunities in CNS agent discovery in the current efforts ofclinical development for neuropsychiatric disorders difficultThus the increase in promiscuity of drug-target interactionsmakes the discovery of CNS agents more complex

4 Other Aspects in Drug-Target Interactions

We also should consider some other aspects that can provideus with the insights into the scope of CNS agent discoveryFirst two important aspects are functional selectivity and


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[132ndash135]


[136ndash138]


[139]




8 Conclusions








Disclosure


Competing Interests


Acknowledgments


References


























































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















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Chlo

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Side effects

Adrenergic

Muscarinic

Weight gain

110100

100010000

Ki


5-HT2A5-HT2C

5-HT3

5-HT5

5-HT6

5-HT7

D1

D2

D2

D3

D4

D5


H1

H2

H3

H4






Dopamine receptors


Serotonin receptors



M5 antagonists



Glutamate receptors


Others
















Ergotamine tartrate

Phentemine

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Norfluoxetine

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101

10100100010000

Ki (nm)

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Aden

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[132ndash135]


[136ndash138]


[139]




8 Conclusions








Disclosure


Competing Interests


Acknowledgments


References


























































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















Dopamine receptors


Serotonin receptors



M5 antagonists



Glutamate receptors


Others
















Ergotamine tartrate

Phentemine

Fluoxetine

Norfluoxetine

(+) Norfenfluramine


101

10100100010000

Ki (nm)

EP-3

EP-1

Aden

osin

e A2

Aden

osin

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[132ndash135]


[136ndash138]


[139]




8 Conclusions








Disclosure


Competing Interests


Acknowledgments


References


























































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



























Ergotamine tartrate

Phentemine

Fluoxetine

Norfluoxetine

(+) Norfenfluramine


101

10100100010000

Ki (nm)

EP-3

EP-1

Aden

osin

e A2

Aden

osin

e A1

1205721B

1205721A

1205732

1205731

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1205722A AM

PAPC

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[132ndash135]


[136ndash138]


[139]




8 Conclusions








Disclosure


Competing Interests


Acknowledgments


References


























































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



























[132ndash135]


[136ndash138]


[139]




8 Conclusions








Disclosure


Competing Interests


Acknowledgments


References


























































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






















Disclosure


Competing Interests


Acknowledgments


References


























































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






















































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















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