THERAPEUTICSTRATEGIES

DRUG DISCOVERY

TODAY

Drug Discovery Today: Therapeutic Strategies Vol. 3, No. 4 2006

Editors-in-Chief

Raymond Baker – formerly University of Southampton, UK and Merck Sharp & Dohme, UK

Eliot Ohlstein – GlaxoSmithKline, USA

Nervous system disorders

NK3 receptor antagonists for thetreatment of schizophreniaHerbert Meltzer1,*, Adam Prus2

1Vanderbilt University Medical Center, Nashville, TN, USA2Northern Michigan University, Marquette, MI, USA

The ability of NK3 receptor antagonists to enhance

dopaminergic, serotonergic, noradrenergic, choliner-

gic and GABAergic release in the limbic system, cor-

tex, hippocampus and striatum, all of which have been

implicated in schizophrenia and the mechanism of

action of antipsychotic drugs, is a principal reason for

interest in this class of drugs as a possible monotherapy

or augmentation treatment for schizophrenia. In addi-

tion, two NK3 receptor antagonists, osanetant and

talnetant, have been studied in patients with schizo-

phrenia, with some evidence for efficacy (osanetant).

*Corresponding author: H. Meltzer (Herbert.meltzer@vanderbilt.edu)

1740-6773/$ � 2006 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.ddstr.2006.11.013

Section Editors:David Sibley – National Institute of Neurological Disordersand Stroke, National Institutes of Health, Bethesda, USAC. Anthony Altar – Psychiatric Genomics, Gaithersburg,USATheresa Branchek – Lundbeck Research, Paramus, USA

Introduction

Schizophrenia is a neurodevelopmental disorder that gener-

ally develops during late adolescence but may also rarely first

manifest itself in childhood, early adolescence or much more

rarely in the fourth and fifth decades of life. Multiple genes

contribute to the vulnerability to develop schizophrenia, but

it must be noted that identical twins are concordant for

schizophrenia only 50% of the time, indicating that environ-

mental factors must be important in the pathogenesis of this

disorder [34]. Although a plethora of genes have now been

associated with schizophrenia, the etiology of schizophrenia

is unknown but is believed to involve both cellular and

neurochemical abnormalities [9]. There are no reliable diag-

nostic tests or biomarkers for schizophrenia. The main feature

of schizophrenia, which leads to devastating decline in social

and vocational function, is cognitive impairment [30]. This

develops some time before the onset of psychosis, leading, on

average, to a 10–15-point deficit in IQ, accompanied by

performance 1–2 standard deviations below normal in cog-

nitive tests. This cognitive deficit is almost universally per-

sistent and gradually increases in most patients during the

course of the illness. Delusions, hallucinations and bizarre

behavior, which are collectively referred to as positive symp-

toms, are usually episodic in patients with schizophrenia. A

third cluster of symptoms associated with schizophrenia are

negative symptoms, comprisinf flat affect, anhedonia, loss of

motivation and anergia.

Current therapies for schizophrenia: antipsychotic

drugs

Although diverse in nature and chemical structure, all cur-

rently approved antipsychotic drugs share the common trait

of reducing dopaminergic function by either direct dopamine

(DA) D2 receptor antagonism or D2 receptor partial agonism

[24]. The role of D1, D3 and D4 receptors in schizophrenia and

its treatment is much less understood. There are no known

therapies of schizophrenia that are based on D1, D3 or D4

receptor interactions, with the possible exception that the

substituted benzamides, such as amisulpride, have a high

affinity for both the D2 and D3 receptors. Excessive release

of DA in the mesolimbic DA terminal regions is believed to

555

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Table 1. Antipsychotic drugs: NK3 receptor antagonists compared with D2 and 5-HT2/D2 receptor compounds

Drug class Pros Cons Latest developments Who is working on this strategy Refs

NKa3 antagonists Produces effects on dopaminergic

neurotransmission that may be important

for treating positive, negative and cognitive

symptoms; some clinical data suggesting

efficacy on positive symptoms; low

liability for extrapyramidal side effects, plasma

prolactin elevations and weight gain.

Preclinical models are not

unequivocally predictive of

clinical benefit in

schizophrenia; most work is in

guinea pigs; there are few

published clinical studies;

clinically tested NK3

antagonists demonstrate poor

bioavailability; clinical efficacy

for negative and cognitive

symptoms unknown.

At least three companies are actively

investigating this mechanism for

schizophrenia; osanetant was

withdrawn from Phase II trials

by Sanofi-Aventis due to a lack

of improved efficacy at higher

doses; talnetant is in Phase II clinical

trials by GlaxoSmithKline.

Sanofi-Aventis

(http://www.sanofi-aventis.us/);

GlaxoSmithKline

(http://www.gsk.com/);

Roche (http://www.roche.com/).

[5,7,19,20,

27,37]

5-HT2b/D2

antagonists

Proven mechanism to produce antipsychotic

efficacy with minimal EPSc at clinically

effective doses; clozapine effective in treatment

resistant schizophrenia and to reduce risk

for suicide; low risk for tardive dyskinesia;

are more effective for negative symptoms

and and cognitive deficit compared with

typical antipsychotic drugs.

Efficacy for negative symptoms and

cognition on mild-moderate end;

olanzapine and clozapine are

associated with moderate-severe

metabolic side effects, including

weight gain, glucose dysregulation

and lipid increases.

Several companies are developing

5-HT2A/D2 antagonists that do not

block 5-HT2C or H1 receptors to

avoid weight gain; adjunctive therapies

are being pursued by adding 5-HT1A

receptor stimulation ampakines, or

muscarinic M1 receptor stimulation

to 5-HT2A/D2 receptor antagonist effects.

New entities of this type are

being developed by Lundbeck,

Merck (http://www.merck.com/);

Pfizer (http://www.pfizer.com/);

Organon (http://www.organon.com/).

[8,11,21,23]

D2 partial

agonists

Treat positive and negative symptoms,

and have low liability for EPS or

metabolic side effects

There is limited evidence for the

cognitive efficacy of these drugs

D2 partial agonists are being developed

to also act as inverse agonists at 5-HT2

receptors and as agonists at 5-HT1A

receptors; bifeprunox is a 5-HT1A

agonist/D2 partial agonist developed

by Solvay and Wyeth; NDA submitted

in past quarter 2006.

Parke-Davis [now a subsidiary of Pfizer

(http://www.pfizer.com/)];

Solvay

(http://www.solvaypharmaceuticals.com/);

Wyeth (http://www.wyeth.com/).

[3,29]

APD, antipsychotic drugs.a Neurokinin.b Serotonin.c Extrapyramidal side effects.

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Vol. 3, No. 4 2006 Drug Discovery Today: Therapeutic Strategies | Nervous system disorders

contribute to psychosis [24]. Conversely, diminished release

of DA in the frontal cortex and hippocampus has been related

to cognitive impairment and negative symptoms [22]. Thus,

the treatment of schizophrenia has focused on the methods

to block limbic D2 DAergic function and to enhance stimula-

tion of D1, and perhaps other types of DA receptors, in the

cortex.

The first antipsychotic drugs developed, for example,

chlorpromazine and haloperidol, have been shown to act

through D2 receptor antagonism [24]. Striatal D2 receptor

blockade is responsible for extrapyramidal side effects (EPS),

including parkinsonism, dystonias and tardive dyskinesia

[24]. D2 receptor antagonists, sometime referred to as typical

neuroleptics or first-generation antipsychotic drugs, signifi-

cantly improve positive symptoms but not cognition or

negative symptoms.

Clozapine, a dibenzodiazpine, was the first drug shown to

be able to improve psychosis without causing significant EPS

in almost any patient at any dose [11]. Clozapine was subse-

quently shown to improve psychotic symptoms in patients

who failed to respond to haloperidol and related drugs, to

improve negative symptoms, albeit weakly, to improve some

domains of cognition and to reduce the risk of suicide [8,23].

The ability of clozapine and other related atypical antipsy-

chotic drugs, including olanzapine, quetiapine, risperidone

and ziprasidone, to improve cognition has been suggested to

be due, in part, to their ability to enhance the efflux of DA and

acetylcholine (ACh) in the frontal cortex and hippocampus

[10,15]. Pharmacologically, clozapine is a very complex drug

with a multiplicity of relatively high affinity pharmacologic

actions on serotocepters, muscarinicocepters, DAcepters and

noradrenoceptors [31]. The most widely accepted explana-

tion for many of its actions, based in part on the shared

pharmacology with other atypical antipsychotic drugs, is the

hypothesis that some of its key advantages are due to more

potent serotonin (5-HT)2A than D2 receptor blockade [21].

This contributed to the development of a series of structurally

diverse compounds with similar dual actions on 5-HT2A and

D2 receptors, including olanzapine, ziprasidone, risperidone,

zotepine and quetiapine. These are sometimes referred to as

5-HT2/D2 antagonists (see Table 1). In fact, these compounds

are inverse agonists at the 5-HT2A receptors, indicating their

ability to block constituitive activity of the 5-HT2A receptor.

Aripiprazole is another type of atypical antipsychotic drug

that exhibits partial agonistic activity at DA D2 receptors

rather than direct D2 receptor antagonism in addition to 5-

HT2A inverse agonism [3]. In its case, partial D2 receptor

agonism is substituted for direct D2 antagonism. It has been

found to be similar to the 5-HT2/D2 antagonists in efficacy

[29], although its ability to improve cognition has not been

satisfactorily demonstrated to date. However, it has minimal

liability to produce EPS or metabolic side effects, which is one

of the reasons for its rapid adoption (see Table 1). The

relatively modest efficacy of typical or atypical antipsychotic

drugs to treat many aspects of schizophrenia, especially

cognition and negative symptoms, has made the search for

novel treatments of great importance. Recently, the notion

that multiple classes of drugs may be needed to treat this

syndrome or that drugs with very complex pharmacology

which can simultaneously interact with multiple targets, be

they receptors, other proteins or genes themselves, has led to

the search for drugs that may augment rather than replace the

current generation of antipsychotic drugs.

Neurokinins

The tachykinin peptide family and their receptors

Substance P (SP), Neurokinin (NK)A and NKB (NKA and NKB)

comprise the tachykinin family, an evolutionarily conserved

family of peptide neurotransmitters, which is present in brain

[33]. There may well be other tachykinins that have not yet

been characterized. The tachykinins are widely expressed in

both the central and the peripheral nervous system [4,13].

The distinguishing characteristic of tachykinins is their com-

mon carboxy terminal amino acid sequence, Phe–X–Gly–

Leu–Met–NH. In the case of Substance P, X is an aromatic

residue, whereas it is a branched aliphatic for NKA and NKB

[28]. The preprotachykinin A (PPT-A or TAC-1) gene (GenBank

accession no. NM_013998) gives rise to SP and NKA by

alternate RNA splicing and tissue specific processing [28].

The preprotachykinin B (PPT-B or TAC-3) gene (GenBank acces-

sion no. NM_013251) is the precursor of NKB [1,26,28].

SP, NKA and NKB mediate their effects through NK1, NK2

and NK3 receptors, respectively, which are all G-protein-

coupled receptors [26]. The genes for these receptors are

similar [1,18,26], comprising five exons, with introns inter-

rupting the coding sequences in identical positions. Endo-

genous mammalian tachykinins are able to bind and act as

full agonists, albeit with different potencies, at each of the NK

receptors [1,25,32]. SP is most potent as an agonist at the NK1

receptor and least at the NK2 and NK3 receptors. NKA is most

potent as an agonist at the NK2 receptor and intermediate at

the NK2 and NK3 receptors. NKB is most potent as an agonist

at the NK3 receptor and least effective at the NK1 receptor

[25]. Senktide is a highly selective and potent agonist at the

NK3 receptor and has been used extensively to study the role

of NK3 receptors and to facilitate the study of putative NK3

antagonists [16].

NK3 receptor expression and function

NK3 receptors are localized mainly in the central nervous

system and spinal cord [16,26]. NK3 receptors, like NK1

receptors, are more abundant in the brain than NK2 receptors

[16,26]. NK3 receptors have been found mainly in cortical

regions, including the frontal, parietal and cingulate

cortex, various nuclei of the amygdala, the hippocampus,

basal forebrain [7,16] and midbrain structures such as the

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Drug Discovery Today: Therapeutic Strategies | Nervous system disorders Vol. 3, No. 4 2006

substantia nigra (SN), ventral tegmental area (VTA) and raphe

nuclei [16,32,36]. NK3 receptors have also been demonstrated

to be present on basal forebrain gamma-aminobutyric acid

(GABA) neurons that project to the frontal cortex and on

basal forebrain cholinergic neurons that project to the pri-

mary motor and somatosensory cortices [7]. In situ hybridiza-

tion revealed co-expression of NK3 receptors with nitric

oxide synthase/preprosomatostatin containing GABAergic

interneurones [13].

The DA neurons in the SN and VTA are known to be

important for extrapyramidal function and for the antipsy-

chotic and cognitive enhancing effects of action potential

durations [9,24]. NK3 receptors have been found on DA

neurons in the SN and VTA [16,36]. Consistent with this,

senktide has been shown to excite dopaminergic neurons in

the SN and VTA [12,32]. The excitatory action of senktide on

dopaminergic neurons is blocked by the selective NK3 recep-

tor antagonist osanetant (Sanofi-Aventis, http://www.sanofi-

aventis.us/) but not by NK1 or NK2 receptor antagonists [27].

NK3 receptors and interaction with dopamine, serotonin,

noradrenaline, acetylcholine and GABA neurons

Administration of senktide enhances DA outflow in terminal

regions due to direct excitation of DA neurons. Thus, local

administration of senktide by reverse dialysis into the VTA

and SN pars compacta, significantly enhanced extracellular

DA efflux in guineas pig nucleus accumbens, prefrontal

cortex and striatum in vivo [19,27]. Behavioral studies pro-

vided further evidence that NK3 receptor agonists enhance

dopaminergic function. Increased locomotion, sniffing and

rearing, which is known to be associated with enhanced

striatal DA release, has been observed following infusion

of senktide into the SN and VTA [38]. Systemic administra-

tion of senktide has also been reported to increase locomotor

activity, which can be blocked by the NK3 receptor antago-

nist SSR146977 [5]. SSR146977, (R)-(N)-[1-[3-[1-benzoyl-3-

(3,4-dichlorophenyl)piperidin-3-yl]propyl]-4-phenylpiperi-

din-4-yl]-N-dimethylurea, is a potent and selective antago-

nist of the tachykinin NK3 receptor. It has been reported to

block the senktide-induced increase in firing rate of the

dopaminergic neurons in the guinea pig SN as well as to

block the senktide-induced increase in activity of noradre-

nergic neurons in the guinea pig locus coeruleus, which

increases extracellular levels of NE, increase in the prefrontal

cortex [2].

The selective NK3 receptor agonist senktide elicited yawn-

ing, chewing mouth movements and sexual arousal at doses

of 0.1–1.0 mg/kg subcutaneously (sc) in the rat [37]. These

responses were significantly inhibited by the peripheral and

central muscarinic antagonist scopolamine but not by the

peripheral muscarinic antagonist, N-methylscopolamine,

haloperidol, a D2 antagonist, nor lesions of the nigro-striatal

DA neurons. Further evidence that NK3 receptors promote

558 www.drugdiscoverytoday.com

muscarinic and possibly nicotinic cholinergic receptor activ-

ity, stimulation of NK3 receptors by systemic administration

of senktide has been shown to dose-dependently increase

levels of ACh release in the hippocampus, an effect which is

prevented by pretreatment with the NK3 receptor antagonist

SSR146977 [5]. The local application of the NK3 tachykinin

receptor agonist senktide in the area of cholinergic cell bodies

(septal area) markedly enhanced the extracellular ACh

concentration throughout the hippocampus [5,19].

When injected intracerebroventricularly or directly into

the raphe area, senktide elicits the ‘serotonin syndrome’, for

example, head twitches, forepaw treading, wet dog shakes

and hindlimb splaying [37]. This activation of the raphe

nuclei appears to be an indirect effect owing to an effect

on local glutamatergic circuitry [17]. Stimulation of NK3

receptors may cause inhibitory or excitatory effects on cor-

tical and hippocampal pyramidal neurons that play a critical

role in cognition [6,9]. The release of 5-HT by NK3 receptor

stimulation and its possible inhibition by an NK3 receptor

antagonist would be expected to indirectly affect a variety of

5-HT receptors, including the 5-HT1A, 5-HT2A and 5-HT2C

receptors, all of which have been implicated in the action of

antipsychotic drugs.

Significant GABA release also was observed when striatal

slices were challenged with the NK3 receptor agonist senktide,

an effect that was blocked by the NK3 receptor antagonist

osanetant [7]. These findings suggest that tachykinins mod-

ulate GABA release within the striatum via interaction with

NK3 receptors on somatostatin/nitric oxide synthase inter-

neurones.

These considerations indicate that activation of NK3

receptors leads to activation and release of biogenic amines

dopamine, serotonin, noradrenaline, GABA and ACh. The

impact on psychosis and cognitive function of these effects is

impossible to predict at this time. The net effect will depend

on the basal and stimulated levels of these amines in specific

areas of the brain, in each patient, and at what phase of their

illness they may be, for example, prodromal, first episode,

chronic and unstable or chronic and stable. In some cases, for

example, patients with stable chronic schizophrenia with

predominantly cognitive and negative symptoms, enhanced

release of cortical or hippocampal DA, norepinephrine or

ACh may be beneficial. In patients with acute episodes,

enhanced release of DA in the limbic system may, in fact,

be harmful. In this instance, reduction in NK3 mediated

excitation by drugs such as osanetant and talnetant would

be expected to reduce the release of dopamine in ventral and

dorsal striatal regions, which should have a positive effect on

psychosis. Diminished release of 5-HT might tend to potenti-

ate the effect of 5-HT1A receptor stimulation or 5-HT2A

receptor antagonism, key features of atypical antipsychotic

drugs such as clozapine and quetiapine, and, thus, lead to

better response. This is one of the reasons for considering

Vol. 3, No. 4 2006 Drug Discovery Today: Therapeutic Strategies | Nervous system disorders

Outstanding issues

� Will NK3 antagonists have efficacy as antipsychotic agents?

� Will NK3 antagonists be stand-alone treatments for psychosis or

other features of schizophrenia such as cognitive impairment, be

able to facilitate the efficacy of typical or atypical antipsychotic drugs

or be ineffective in either capacity?

� Does osanetant or talnetant have any efficacy in treating

schizophrenia?

� Are there other novel NK3 antagonists with better bioavailability

and pharmacokinetic properties that can provide a valid test of the

NK3 hypothesis?

use of the NK3 antagonists as augmentation agents for the

treatment of schizophrenia (see Outstanding issues).

Clinical evidence for an action of NK3 receptor antagonists

As discussed above, osanetant is a selective NK3 receptor

antagonist, which has been shown to block the ability of

senktide, a selective NK3 agonist, to enhance forebrain DAer-

gic function in vivo and in vitro [5]. Osanetant was one of the

four novel compounds compared with haloperidol and pla-

cebo in a 6-week randomized double-blind trial in recently

hospitalized, acutely psychotic patients with schizophrenia

or schizoaffective disorder [20]. The three other investiga-

tional drugs studied along with osanetant were the 5-HT2A/C

antagonist (SR46349B), a central cannabinoid (CB1) antago-

nist (SR141716) and a neurotensin (NTS1) antagonist

(SR48692). A total of 481 patients were randomly assigned

to placebo or haloperidol (N = 98 per group) or one of the four

experimental compounds (N = 69–74 per group). The dose of

osanetant was 200 mg/day. Both haloperidol and osanetant,

but not the neurotensin agonist or CB1 antagonist, differen-

tiated from placebo. The haloperidol- and osanetant-treated

group showed significantly greater improvement at 6 weeks

in total psychopathology, positive symptoms and the mea-

sure of global clinical improvement. The improvement in the

haloperidol-treated patients was not significantly different

from that found with osanetant. Response to osanetant cor-

related with plasma levels, suggesting that higher doses of

osanetant, or another NK3 antagonist with better bioavail-

ability, might be more effective than was noted in this study.

An informal report of a follow-up study, using higher doses of

osanetant has been issued by Sanofi, indicating negative

results, leading to the decision not to continue the develop-

ment of this compound for schizophrenia at this time. How-

ever, the details of this study have not been released. The

option of studying other NK3 antagonists for schizophrenia

by Sanofi was not excluded. Osanetant has also been reported

to be ineffective in a placebo-controlled trial of patients with

panic disorder [14].

Talnetant (GlaxoSmithKline, http://www.gsk.com/), an-

other NK3 receptor antagonist, as noted above, has also been

tested in schizophrenia. Some information released at a

financial conference indicated that it was effective to improve

positive symptoms and, possibly, cognition, in 20 patients

with schizophrenia, with no evidence that it caused EPS,

plasma prolactin elevations or weight gain. However, until

these data have been reviewed and published, they should

not be taken as evidence for or against the possibility that

talnetant is effective and tolerable in treating patients with

schizophrenia. Additional studies with talnetant to establish

efficacy for schizophrenia have been completed, but there is

no public information as to the results of these trials. It

should be noted that osanetant does not have ideal charac-

teristics as a treatment. It appears to have pharmacokinetic

and bioavailability problems. In particular, it may be cleared

too rapidly. Talnetant may not pass the blood brain barrier

sufficiently readily to be effective. Therefore, there is a need

for other NK3 antagonists with acceptable pharmacokinetic

properties, bioavailability and ability to pass the blood brain

barrier before any conclusion can be reached as to the utility

of this mechanism to treat schizophrenia. It may be that

although NK3 antagonists are inadequate as monotherapy,

they may be useful as augmentation agents for atypical or

first-generation antipsychotic drugs. Their lack of significant

side effects and ability to modulate cortical DA, which would

be expected to improve cognition and possibly negative

symptoms, is suggestive of their suitability as adjunctive

therapy. Talnetant and osanetant are discussed in more detail

elsewhere [35].

Summary and conclusions

In summary, NK3 receptor stimulation has been shown to

enhance dopaminergic, noradrenergic, serotonergic,

GABAergic and cholinergic activity in various animal models,

in a way that could be consistent with improving psychosis or

cognition in schizophrenia. However, the clinical evidence in

support of these potential benefits of NK3 antagonists, osa-

netant and taletant, at this time, is limited (see Outstanding

issues). Indeed, only one of the completed clinical studies of

these compounds, osanetant, has been published [20] or

otherwise released for scrutiny by the scientific community.

The efficacy of the NK3 antagonists, osanetant and talnetant,

may be limited more by pharmacokinetic problems asso-

ciated with these two exemplars rather than pharmacody-

namic limitations of the NK3 target. It is hoped that further

information about the extant clinical data will be made

available shortly, with the goal of determining future

research directions for pursuing what appears to be a promis-

ing target for the treatment of schizophrenia.

Acknowledgements

Supported, in part, by grants from the William K Warren

Foundation, Ritter Foundation and Stanley Medical Research

Institute.

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