investigational nmda receptor modulators for depression

1. Introduction

2. General overview of the NMDA

receptor

3. The role of NMDA receptor

antagonists in the therapy of

depression

4. The metabotropic glutamate

5 receptors as NMDA receptor

modulators

5. Expert opinion

Review

Investigational NMDA receptormodulators for depressionBernadeta Szewczyk, Agnieszka Pałucha-Poniewiera, Ewa Poleszak,Andrzej Pilc & Gabriel Nowak††Institute of Pharmacology, Polish Academy of Sciences, Department of Neurobiology, Krakow,

Poland

Introduction: With regards to depression, the role of N-methyl-D-aspartate

receptor (NMDA) was pursued many years ago, mainly in the form of preclinical

studies. Since then, there have been several clinical data in the literature indi-

cating the efficacy of NMDA receptor antagonists of either stand-alone or as

an adjunct therapy in depression and depression-related diseases.

Areas covered: The present review focuses on clinical data of well-known

and recently discovered NMDA receptor antagonists/modulators and their

mechanisms of action.

Expert opinion: Several NMDA receptor modulators have been tested in both

human and animal studies to examine their potential antidepressant activity.

Most of the compounds that exhibited beneficial properties in the animal tests

and models of depression either have never been tested or did not show effi-

cacy in humans. For some of them, such as ketamine, where a consistently

reproducible antidepressant effect was found, clinical use is limited by a variety

of adverse effects. However, ketamine has become a standard tool for identify-

ing the biological factors associated with rapid antidepressant action and, as

such, is a novel target for the development of new therapeutics.

Keywords: antagonist, antidepressants, depression, ketamine, magnesium, metabotropic

glutamate receptor, NMDA receptor, zinc

Expert Opin. Investig. Drugs [Early Online]

1. Introduction

Several lines of evidence coming from both preclinical and clinical studies indicatethat glutamate homeostasis and glutamate neurotransmission play an important rolein physiology and are deregulated in depressive disorder [1-4].

From several types of glutamate receptors, the contribution of theN-methyl-D-aspar-tate receptors (NMDARs) to depression and antidepressant treatment is evidently dem-onstrated. NMDA receptors belong to the large family of ionotropic glutamate (iGlu)receptors that mediate excitatory synaptic transmission throughout the central nervoussystem thus being fundamental to the regular brain functions (Table 1). Because oftheir involvement in excitotoxicity as well as in neurodegenerative, neurological andpsychiatric disorders, NMDARs are also targets of therapeutic interest.

The hypothesis that NMDA receptor modulators could have a clinical applicationwas based on a significant amount of preclinical evidence. It was found that the com-petitive NMDA antagonist at glutamatergic sites (2-amino-7-phosphonoheptanoicacid; AP-7), a channel blocker (dizocilpine; MK-801), a partial agonist at strychnine-insensitive glycine sites (1-aminocyclopropanecarboxyli acid [ACPC]) and the selectiveantagonist of NR2B receptor subtype (eliprodil) were active in the forced swim test(FST) and tail suspension test (TST) in mice [5,6]. The competitive antagonist at gluta-matergic sites (CGP 37849 and CGP 39551), channel blockers (dizocilpine, amanta-dine and memantine), ACPC and the antagonist at glycine sites (7-chlorokynurenicacid) were active in the FST in rats [7-10]. CGP 37849, dizocilpine, memantine and

10.1517/13543784.2012.638916 © 2011 Informa UK, Ltd. ISSN 1354-3784 1All rights reserved: reproduction in whole or in part not permitted

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ACPC were active in chronic mild stress in rats [11] and inchronic unpredictable stress in rats [12,13]. Research into theantidepressant-like effects of NMDA receptor antagonists tooka very important turn in 2000 when Berman et al. [14] publisheda study about the rapid and robust antidepressant response inpatients diagnosed with major depression to the ketamine infu-sion. These results have initiated a number of studies on themechanism of action of ketamine and in turn the new factorsinvolved in the pathophysiology and treatment of depressionas well as new clinically safer modulators of the NMDAreceptors were identified.

2. General overview of the NMDA receptor

TheNMDA receptor functions as a heterotetramer composed offour subunits (3 full transmembrane and one intramembraneloop) that form a central cation-selective pore (Figure 1).Molecular studies have clearly shown a significant diversity ofNMDA subunits as well as a multiplicity of their possible com-positions. Three families of NMDA receptor subunits have beenidentified by molecular cloning: GluN1 (with eight distinct iso-forms), GluN2 (GluN2A, B, C and D) and GluN3 (GluN3Aand B) (formerly NR1, NR2 and NR3) [15]. Each receptor sub-unit is composed of four domains that include the extracellularamino-terminal domain, the extracellular ligand bindingdomain, the transmembrane domain, and an intracellularcarboxyl-terminal domain. NMDA receptor is usually formedof two NR1 and two NR2 subunits (NR1/NR2 complex).However, many other possible combinations of NMDA recep-tor subunits exist. Differential molecular architecture of theNMDA receptors implies distinct functional properties andregulation [16-19].NMDA receptor activation depends on the unique

mechanism of receptor channel gating both by ligands and

by voltage. The simultaneous binding of two distinct agonists,glycine to NR1 (at the GLYB site) and glutamate to NR2, isrequired for activation of the NMDA receptor [20]. The volt-age dependence, on the other hand, is caused by the Mg2+

block within the ion channel [21,22].The NMDA receptor can be regulated by not only compet-

itive ligands but also by open channel blockers as well as byallosteric modulators. Open channel blockers, termed uncom-petitive antagonists, require an open receptor pore to allowaccess to the binding site to cause subsequent antagonism ofreceptor activity [23]. Thus, inhibition of the NMDA receptorby uncompetitive antagonists depends on the probabilityof the NMDA receptor channel opening. UncompetitiveNMDA receptor antagonists include Mg2+, polyamines,phencyclidine, ketamine, dizocilpine, memantine, amanta-dine, pentamidine and dextromethorphan. Some channelblockers can be trapped inside the channel after its closingand they dissociate slowly only after the channel’s reactivationby agonists. Such compounds are named trapping blockers(e.g. ketamine, phencyclidine, dizocilpine). Another groupof channel blockers comprises partially trapping blockers(e.g., memantine, amantadine), which bind after channelopening and unbind rapidly, which has been proposed to betherapeutically beneficial since these compounds may notinfluence normal synaptic transmission, although they dodecrease overactivation of the receptor [24,25].

The NMDA receptor, similarly to other iGlu receptors, isalso regulated by allosteric modulators, which modify theexisting level of receptor activation rather than either overacti-vate or permanently block its activity. Moreover they display ahigher potential for receptor subtype selectivity, because theyoften target less conserved regions than the agonist bindingsite and are believed to be more tolerated than competitivecompounds. Therefore, allosteric modulators are thought tohave therapeutic advantages over agonists and competitiveantagonists of the NMDA receptor.

Apart from the above noted voltage-dependent activity ofpolyamines inside the channel of the NMDA receptor, theyalso act at the extracellular modulatory site and enhanceNMDA receptor responses in a voltage-independent mannerby both the direct modulation of glycine’s interac-tions with the NMDA receptor complex as well as by theglycine-independent mechanism [26-28].

Another modulator of NMDA receptor activity is Zn2+. Itsactivity is biphasic and depends on the synaptic concentra-tion: at low concentrations (IC50 10 -- 30 nM) it induceshigh-affinity voltage-independent inhibition and at high con-centrations (IC50 20 -- 100 µM) it engenders a low-affinity voltage-dependent channel block [29-31]. Activity ofthe NMDA receptor is also regulated by protons, whichinhibit receptor functions by reducing open channel probabil-ity and open channel duration. Proton inhibition is indepen-dent of voltage and ligand binding [32,33]. On the other hand,reducing agents, such as dithiothreitol, have been shown toreversibly potentiate NMDA receptor function [34]

Article highlights.

. NMDA receptor is modulated by competitive ligands,open channel blockers and allosteric modulators.

. Evidence is mounting that agents targeting the NMDAreceptor may be the key to developing a newgeneration of improved antidepressants.

. Ketamine with its rapid antidepressant response hasbecome a standard tool for identifying the biologicalfactors associated with rapid antidepressant action and,as such, is a novel target for the development of newtherapeutics for depression.

. Clinical trials of some subtype selective NMDA receptorantagonist for treatment of depression have progressedto Phase I and Phase II.

. Results obtained for zinc in depression suggest thatNMDA antagonists might be an alternative therapy forimproving depression in patients resistant toconventional antidepressants.

This box summarizes key points contained in the article.

Investigational NMDA receptor modulators for depression

2 Expert Opin. Investig. Drugs [Early Online]

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Table

1.Recentclinicaldata

aboutNMDA

receptor-modulatingdrugsin

thetreatm

entofdepression.

Compounds

Clinicaldata

Ref.

Ketamine

Arandomized,placebo-controlled,double-blindtrialto

assess

theeffect

ofasingle

dose

ofketaminein

depression

7subjects;

0.5

mg/kgasaketaminehydrochloride,intravenous

infusion

Results:

significantim

provementin

depressivesymptoms(decreasedHDRSsore)within

72hafterketaminebutnotplaceboinfusion

Berm

anetal.,2000

[14]

Arandomizedplacebo-controlled,double-blindcrossoverstudyofketaminein

treatm

ent-resistantMDD

18subjects(9

placebos;

9ketaminehydrochloride0.5

mg/kgasanintravenousinfusion)

Ratingtime:40,80,110,230min

and1,2,3,7

days

post-infusion

Results:

significantim

provement(decreasedHDRS)obtainedwithin

110min

afterasingle

dose

thatcontinuedto

remain

significantfor1week

Zarate

etal.,2006

[35]

Thestudyinvestigatedtherole

ofafamily

history

ofalcoholdependence

ontheketamine’s

initialantidepressanteffect

intreatm

ent-resistantMDD

26patients;0.5

mg/kg;ratingtime:40,80,120,230min

post-infusion

Results:

significantim

provement(decreasedMADRSscores)

insubject

withafamily

history

ofalcoholdependence

Phelpsetal.,2009

[36]

Theclinicalstudyexaminedtheeffect

ofasingle

dose

ofketamineonsuicidalideationin

patients

withtreatm

ent-resistantMDD

33patients;0.5

mg/kg;ratingtime:40,80,120,230min

post-infusion

Results:

suicidalideationin

thecontext

ofmajordepressionim

provedwithin

40min

(decreased

SSIscores)

andremainedim

provedforupto

4hpost-infusion

Depression,anxiety

andhopelessness

were

improvedatalltimepoints

(decreasedMADRS,

HDRSandBDIscores)

DiazG

ranadosetal.

2010

[37]

Thestudyexaminedtherole

ofketaminein

patients

withdepression,whodid

notrespond

toECT

40patients

(17-did

notrespondto

ECTand23neverreceivedECT)

Ketamine0.5

mg/kg,ratingtime:40,80,120,230min

post-infusion

Results:

significantim

provementin

theECT-resistantgroup

Ibrahim

etal.,2011

[39]

Aretrospectivesingle-centerstudyofketamineasananestheticforECTin

therapy-resistant

depression

42patients

receivingECTtreatm

entwithketamine(16)orthiopental(26)

Results:

TheketaminegroupneededsignificantlyfewerECTsessionsandhadlower

HAM-D

scores

Kranasteretal.2011

[41]

BDI:Beck

depressioninventory;ECT:Electroconvulsivetherapy;

HAM-A:Hamiltonratingscale

foranxiety;HDRS,HAM-D:Hamiltondepressionratingscale;IM

I:Im

ipramine;MADRS:Montgomery-asberg

depression

ratingscale;MDD:Majordepressivedisorder;SSI:Scale

forSuicideIdeation.

Szewczyk, Pałucha-Poniewiera, Poleszak, Pilc & Nowak

Expert Opin. Investig. Drugs [Early Online] 3

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Table

1.Recentclinicaldata

aboutNMDA

receptor-modulatingdrugsin

thetreatm

entofdepression(continued).

Compounds

Clinicaldata

Ref.

Memantine

Adouble-blindplacebo-controlledstudyin

patients

withMDD

32subjects;

memantine5--20mg/day

Results:

notreatm

enteffect

Zarate

etal.,2006

[53]

Thestudyofmemantinein

thetreatm

entofMDDin

patients

withcomorbid

alcoholdependence

80subjects(40receivedmemantine20mg/dayand40escitalopram

20mg/day)

Results:

Significantreductionin

thelevelofdepressionandanxiety

accordingto

MADRSandHAM-A

Muhonenetal.2008

[54]

Zinc

Zincsupplementation(daily

dose:25mgZn2+aszinchydroaspartate

+tricyclic

antidepressants

or

selectiveserotonin

reuptakeinhibitors;length

12weeks)

Results:

reducedHDRSandBDIscores

Nowaketal.2003

[56]

Zincsupplementation(daily

dose:25mgZn2+aszinchydroaspartate

+~140mg/dayim

ipramine;

length

12weeks)

Results:

reduceddepressionscoresandfacilitatedtreatm

enteffect

inantidepressanttreatm

ent

resistantpatients

Siweketal.,2009

[57]

Magnesium

Magnesium

treatm

entin

depression(125--300mgwitheach

mealandatbedtime)

EbyandEby,

2006[61]

Magnesium

treatm

entin

thetreatm

entofnewlydiagnoseddepressionin

theelderlywithtype-2

diabetesandhypomagnesemia

(randomizedclinicaltrials)

23patients:tw

ogroupoftreatm

ent:50mlofMgCl 25%

solution(450mgofelementalmagnesium

or50mg/dayofim

ipramine

Results:

magnesium

wasaseffectivein

thetreatm

entofdepressionasIM

I

Barragan-Rodriguezetal.,

2008

[62]

CP-101,606

Traxoprodil

(Pfizer)

Placebocontrolleddouble-blindstudyin

patients

withtreatm

ent-refractory

majordepressivedisorder

30patients

notrespondedto

paroxetine;single

infusionofCP-101,606+paroxetine

Results:

agreaterdecrease

inHDRSin

CP-101,606+paroxetinegroupthanin

placebo+paroxetine

Preskorn

etal.2008

[69]

BDI:Beck

depressioninventory;ECT:Electroconvulsivetherapy;

HAM-A:Hamiltonratingscale

foranxiety;HDRS,HAM-D:Hamiltondepressionratingscale;IM

I:Im

ipramine;MADRS:Montgomery-asberg

depression

ratingscale;MDD:Majordepressivedisorder;SSI:Scale

forSuicideIdeation.



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3. The role of NMDA receptor antagonists inthe therapy of depression

The first clinically used NMDA receptor antagonist was keta-mine. The first placebo-controlled study performed by Bermanin 2000 [14] showed improvement in depressive symptoms inseven patients within 72h after ketamine but not placebo infusionmeasured by the Hamilton Depression Rating Scale (HDRS).This effect was then supported in a study by Zarate et al. [35],who reported the antidepressant efficacy of ketamine in patientswith treatment-resistant depression. It is worth highlighting thatmost of the patients (71%) responded to ketamine administrationwithin 24 h, some (29%) met remission and some (35%) main-tained response for at least 1 week [35]. Rapid antidepressant effi-cacy of a ketamine infusion was also found in resistant depressivepatients with a confirmed family history of alcohol depen-dence [36]; in patients with suicidal ideation in the contextof major depression [37] and in treatment-resistant bipolar

depression [38]. In addition, Ibrahim et al. [39] found the beneficialeffect of ketamine in patients with major depression who hadpreviously not responded to electroconvulsive therapy (ECT),which is still the most effective treatment for depression [40].Kranaster et al. [41] showed the synergistic effect of ketamineand ECT in patients suffering from therapy-resistant depression.The value of ketamine as an antidepressant agent is unfortunatelylimited due to its way of administration (intravenous), and seda-tive and psychotomimetic adverse effects [42,43]. However, therapid antidepressant action produced by ketamine encouragesresearches in investigating the cellular mechanisms responsiblefor this activity. Ketamine’s primary mechanism of action isthe blocking the NMDA receptor at the phencyclidine sidewithin the ionotropic channel [25], although in the context ofantidepressant activity ketamine’s mechanism of action seems tobe more complicated. Recent data suggest that ketamine-mediated antidepressant action required the augmentationof alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid

Channel blockers

Antagonists

NR2A NR1

ZN++

ZN++

Mg++

NR1

NH2 H2N

K+

NR2B

Glutamate

Glutamate binding siteGlutamate binding site

S1

NR 2 subunit NR 2 subunit

HOOC

TM4 TM3 TM2 TM1 TM1 TM3TM2 TM4S1

S2S2

Alternative splicingAlternative splicing

Phosphorylation sites Phosphorylation sites

Glycine

Ifenprodil

Ap5

Mrz 2/576

Ketamine

Phencyclidyne

Memantine

Magnesium ions NMDA receptorMg++

P

PhSh

P PP

Figure 1. Model showing that NMDA receptor functions as a heterotetramer composed of four subunits. Each receptor

subunit is composed of four domains that include the extracellular amino-terminal domain, the extracellular ligand binding

domain, the transmembrane domain, and an intracellular carboxyl-terminal domain. The agonist/antagonist/modulator sites

are depicted.



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receptor (AMPA) activation and increased glutamatergicthroughput of AMPA relative toNMDA [44,45]. The next possibletarget involved in antidepressant activity of ketamine, suggestedin literature is mTOR kinase (the mammalian target of rapamy-cin) [46]. mTOR is a serine-threonine protein kinase that regulatesseveral intracellular processes such as cell growth, cell cycle, andprotein synthesis [47]. There are several data which indicated thekey role of mTOR in several diseases, especially in differenttypes of cancer, cortical dysplasia and neurodegenerativedisorders [47-49]. Recently, Li et al. showed that ketamine rapidlyactivated the mTOR pathway, which resulted in increased synap-tic signaling proteins and increased number and function of newspine synapses in the rat’s prefrontal cortex. Except that, theblockade of mTOR signaling completely blocked the ketamine-induced synaptogenesis and behavioral responses observed in ani-mal models of depression [50]. The next preclinical study per-formed by Autry et al. [44] did not detect the activation ofmTOR signaling after ketamine administration; however, thisstudy varies considerably in terms of methodology. Besides, theway of ketamine administration and tissue preparation in thestudy by Li et al. [50] examined themolecular effects 2 h after keta-mine administration but Autry et al. [44] did their assays after30 min. It is suggested that this time may not be sufficientfor the appearance of changes associated with activation ofmTOR [46], or mTOR activation may be one of the mechanismsresponsible for maintaining the antidepressant effect of ketaminerather than a rapid induction of antidepressant effect of ketamine,which was also suggested by authors [44]. This issue requires fur-ther study. Recently the important role of mTOR signaling inmajor depression was supported by a postmortem study [51],showing a significant reduction in the expression of mTOR andits downstream signaling targets in depressed subjects [51].The next possible mechanism responsible for the rapid

antidepressant action of ketamine raised recently is the rapidsynthesis of the brain-derived neurotrophic factor (BDNF)as an effect due to the blockade of the NMDA receptor atrest and reduced activity of eEF2K (eukaryotic elongation fac-tor 2 kinase) [44], which then influences protein synthesis.This data indicates that regulation of protein synthesis mayserve as a novel therapeutic target for the development ofrapid-acting antidepressants.In contrast to the beneficial effects obtained with ketamine,

the study with memantine, which is a low-affinity, uncompet-itive, open-channel NMDA blocker, was rather controversial.Although in the animal models memantine was found toexhibit antidepressant-like effects [9,52] the clinical study formemantine showed mixed results: no antidepressant effect inthe patients with MDD [53] and potential antidepressant andanxiolytic effects in the patients with MDD and co morbidalcohol dependence [54]. The second study, although morepromising, unfortunately lacked a placebo group, thus limit-ing the value of the results. The possible explanation for thelack of antidepressant activity of memantine, suggested inliterature [2], is the fact that memantine in contrast toketamine is a low-affinity, weak open-channel blocker with

fast off-rates. Moreover, the doses of memantine examinedin the clinical studies may induce a low degree of antagonismof NMDA receptor function to produce antidepressanteffects. However, the exact reason is still not known.

The other NMDA inhibitor for which antidepressant-like activity was reported is zinc [55]. In 2003, Nowak et al. [56]described the effect of zinc supplementation on a group ofpatients with unipolar depression treated by standard antidepres-sant therapy such as tricyclic antidepressants and selective seroto-nin reuptake inhibitors. The analysis of the HDRS and Beckdepression inventory (BDI) scores revealed that patients whoreceived the zinc supplementation of antidepressant treatmentdisplayed much lower scores than patients treated with placebosand antidepressants. Recently, a beneficial effect of zinc supple-mentation was found in treatment-resistant patients [57]. In thisplacebo-controlled, randomized double blind study, zinc supple-mentation augments the efficacy, as well as the speed of the onsetof the therapeutic response to imipramine in treatment-resistant patients. No significant difference in depression scoreswas found between zinc and placebo-supplemented antidepres-sant treatment of non-resistant patients, which suggests the pos-sible involvement of zinc in the psychopathology of drugresistance. The hypothesis that the inhibition ofNMDA receptormay be involved in the antidepressant-activity of zinc was con-firmed by preclinical study. Antidepressant-like effect of zincobserved in the forced swimming test (FST, antidepressant-efficacy screening test) was found to be abolished by NMDA,which is a specific agonist at the NMDA receptor, or by the D-serine co-treatment, which is the agonist of the glycine B site ofglycine/NMDA receptors [58,59]. Furthermore, combined treat-ment of CGP-37849, L-701,324, MK-801 D-cycloserine(NMDA antagonists) and zinc in low and ineffective in FSTdoses, produced a significant reduction of the immobility timein this test [59]. On the other hand, the study using receptorbinding method showed a reduced affinity of glycine toglycine/NMDA receptor after chronic zinc administration [60].

The beneficial effect of magnesium, another uncompetitiveNMDA receptor antagonist, in the treatment of depression wasreported in patients with major depression [61]; in depressedelderly diabetics with hypomagnesemia [62] as well as in patientswithmania [63]; rapid cycling bipolar disorder [64] and fatigue syn-drome [65], disorders which might be related with or may accom-pany depression. Additionally, it was found that supplementinglithium, benzodiazepines and neuroleptics with magnesium sig-nificantly reduced the effective doses of these drugs [66]. Thedata presented above strongly suggest the potential antidepres-sant efficacy of magnesium in the treatment of depression; how-ever to confirm that, much more randomized, double-blind,placebo-controlled clinical trials are needed. The involvementof NMDA/glutamate pathways in antidepressant-like actionof magnesium was shown in FST in mouse [67]. Magnesium-induced antidepressant-like activity observed in this test wasantagonized by NMDA and D-serine co-treatment [58]. More-over, low, ineffective doses of NMDA antagonists such as CGP37849, L-701,324, d-cycloserine, and MK-801 administered



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together with low and ineffective doses of magnesium induces asignificant reduction in immobility time in FST [67].

Using current knowledge about the role of different NMDAreceptor subtypes in physiological and pathological processesas a basis, it appears that compounds acting as the subunit-selective modulators may offer better and safer therapeuticpotential than non-selective NMDA receptor antagonistswhich were found to exhibit a variety of adverse effects [68].

One of these compounds, Ro 25-6981, subunit selectiveNR2B antagonist was found to exhibit a rapid (24 h)antidepressant-like effect in the FST [45,50]. Moreover,Li et al. [50] showed that Ro 25-6981 produced a transientactivation of mTOR signaling similar to ketamine, whichseems to be a new strategy for the development of a fast-actingantidepressants [50].

Recently, a placebo controlled, double-blind study per-formed by Preskorn et al. [69] demonstrated the antidepressanteffect (as an adjunct therapy) of another NR2B subunit-specific NMDA antagonist CP-101,606 (traxoprodil) inpatients with treatment-refractory major depressive disorder.The mechanisms involved in the inhibitory action ofCP-101,606 on the NMDA receptor differ from that describefor ketamine. CP-101,606 makes the receptor more sensitiveto inhibition by protons which serve as an endogenous nega-tive modulator [70]. That CP-101,606 clinical study includedtwo schedules of applications. In the first phase, the subjectsreceived paroxetine for six weeks and a single intravenous pla-cebo infusion after the third week of paroxetine treatment.The paroxetine nonresponders were then randomized andtreated with a single infusion of CP-101, 606 (plus paroxe-tine) or a placebo (plus paroxetine) for the next 4 weeks.The severity of depression was assessed using theMontgomer-y--Asberg Depression Rating Scale (MADRS) and HDRS. Itwas found that, patients receiving CP-101,606 had a graterdecrease in both the MADRS and HDRS scores than placebocontrols, and what is also interesting is 78% of CP-101,606-treated patients maintained the response status for one weekand 32% for 30 days after the infusion [69].

The NIH trial registry (www.clinicaltrials.gov) indicates thatthere are ongoing trials of another NMDA receptor antagonistsuch as EVT101 (Evotec), an NR2B subunit selective antagonist;AZD6765 (AstraZeneca), an NR2A and NR2B subunit antago-nist; GLYX-13 (Naurex), an NMDA glycine-site functional par-tial agonist. For another, NR2B subunit selective NMDAreceptor antagonist MK-0657 (Merck) the phase I clinical trialhas been already completed (www.clinicaltrials.gov).

The role of other NMDA subunits in the pathophysiol-ogy or treatment of depression is also examined. Thepostmortem studies in patients diagnosed with majordepression showed a decreased mRNA [71] and protein [72]

expression of not only NR2B but also at the NR2A sub-unit in the perirhinal cortex and in the anteriorprefrontal cortex, respectively. On the other hand, thepreclinical data showed that NR2A knockout mice exhibitantidepressant-like profiles in the FST and TST [73,74].

Recently a subunit-selective potentiator of NR2Cand NR2D containing the NMDA receptor (CIQ)was identified [75], which allows for the examinationof the role of these two subunits in brain functionand disease.

4. The metabotropic glutamate 5 receptors asNMDA receptor modulators

The metabotropic glutamate 5 receptor (mGlu5) belongsto group I of the large family of metabotropic glutamate(mGlu) receptors. Group I mGlu receptors are coupledpreferentially to phospholipase C, through Gq/11 proteinsand induce phosphoinositide hydrolysis [76]. Group ImGlu receptors predominantly have a postsynaptic locali-zation around iGlu receptors and are associated with theHomer family of proteins, which functionally link groupI mGlu receptors with IP3 receptors, as well as withShank proteins, which function as a part of the NMDAreceptor-associated PSD-95 complex (Figure 2) [77-81]. Thespatial proximity of NMDA and mGlu5 receptors impli-cates their functional relationship. The activation of themGlu5 receptor has been shown to potentiate NMDAreceptor activity [82-85] in the mechanism that requiresG-protein activation[86] and antagonists of mGlu5 recep-tors have been reported to decrease NMDA receptor acti-vation [84]. It has been also shown that the repeateddosing of the mGlu5 receptor antagonist, MTEP (3-[(2-methyl-1,3-thiazol-4-ylethynyl] pyridine) [87], caused a sig-nificant reduction in the expression of the mRNA, encod-ing the NR1 subunit of the NMDA receptor in thecingulate cortex and in the piriform cortex [88]. Thus, com-pounds, which inhibit mGlu5 receptors, may produce afinal effect similar to that evoked by NMDA receptorantagonists, displaying antidepressant-like activity. ThemGlu5 receptor antagonists, which indirectly modulateNMDA receptor function, are another group of potentialantidepressants. Behavioral studies have shown potentialantidepressant-like effects of potent, selective, noncompet-itive and systemically active mGlu5 receptor antagonists:MPEP (2-methyl-6-(phenylethynyl) pyridine) [89] andMTEP. Both compounds shorten the immobility time ofmice in the TST [90-92] and in the FST in mice [93].MTEP was also active in the modified FST in rats [90].Furthermore, both antagonists were tested in the olfactorybulbectomy (OB) model of depression. It has been found,that multiple administrations of MPEP reversed theOB-induced deficits in passive avoidance learning [94,95]

and that repeated administration of MTEP attenuated thehyperactivity of olfactory bulbectomized rats in thistest [91] in a manner similar to the one observed followingchronic (but not acute) treatment with a variety of typicalor atypical antidepressants [96]. Additionally, a lowerdensity and lower protein level of mGlu5 receptors wasfound respectively in untreated depressed patients (PET



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studies) and in the brains of subjects (postmortem studies)diagnosed with major depressive disorder in comparison topsychiatrically healthy subjects [97].

5. Expert opinion

Evidence is mounting that agents targeting the NMDAreceptor may be the key to developing a new generationof improved therapeutics for depression. Following thefirst Berman et al. [14] clinical study in 2000 withketamine (with very few participants) the field becamestagnant; however, after the study of Zarate et al. [35] (pub-lished in 2006) who enrolled a higher number of patients,the interest was markedly renewed. Ketamine with itsrapid antidepressant response is not only the best exampleconfirming this hypothesis but it is also a good tool forstudying the cellular mechanisms responsible for itsfast action. Ketamine’s sedative and psychotomimeticadverse effects, disappointing from one side, has led tothe development of new research for subunit selec-tive NMDA receptor antagonists that will cause fewer

adverse effects but with the same potential as ketamine.Data of zinc and magnesium in depression suggestthat these agents should be tested as supplementaryfactors for lowering the doses of conventionally used anti-depressants and improving its efficacy. Moreover, the datapresented above, indicated that NMDA antagonistsmight be an alternative therapy for improving depressionin patients resistant to conventional antidepressants.

Acknowledgement

B Szewczyk and A Palucha-Poniewiera contributed equally tothis article.

Declaration of interest

The authors have received funding from the Statutory Activityof Institute Pharmacology PAS, Jagiellonian University Med-ical College, Krakow; and the Medical University of Lublin.They state no other potential conflicts of interests forthis article.

Postsynaptic membrane

Postsynaptic cleft

NMDA receptor

PSD

Cytosol

SAPAP/GKAP

ProSAP/Shank

Na+/Ca++

Ca++

NH2 NH2

mGlu receptor

SAP/90/PSD-95

Endoplasmic reticulum

IP3 receptor

Homer CC multimers

IP3 IP3

Ph

Sh

Mg++

Zn++

Figure 2. mGlu5 receptors predominantly have a postsynaptic localization around iGlu receptors and are associated with the

Homer family of proteins, which functionally link mGlu5 receptors with IP3 receptors, as well as with Shank proteins, which

function as a part of the NMDA receptor-associated PSD-95 complex.



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AffiliationBernadeta Szewczyk1,

Agnieszka Pałucha-Poniewiera1, Ewa Poleszak3,

Andrzej Pilc1,4 & Gabriel Nowak†1,2

†Author for correspondence1Institute of Pharmacology,

Polish Academy of Sciences,

Department of Neurobiology,

Smetna 12,

PL 31-343 Krakow, Poland

E-mail: [email protected] University Medical College,

Department of Pharmacobiology,

Medyczna 9,

PL 30-688 Krakow, Poland3Skubiszewski Medical University of Lublin,

Department of Applied Pharmacy,

Staszica 4, PL 20-081 Lublin, Poland4Jagiellonian University Medical College,

Faculty of Health Sciences,

Michałowskiego 20,

PL 31-126 Krakow, Poland



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investigational nmda receptor modulators for depression

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