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Metabotropic Glutamate Receptors for New Treatments in Schizophrenia

  • E. J. Herman
  • M. Bubser
  • P. J. Conn
  • C. K. Jones
Chapter
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 213)

Abstract

Metabotropic glutamate receptors (mGluRs) represent exciting targets for the development of novel therapeutic agents for schizophrenia. Recent studies indicate that selective activation of specific mGluR subtypes may provide potential benefits for not only the positive symptoms, but also the negative symptoms and cognitive impairments observed in individuals with schizophrenia. Although optimization of traditional orthosteric agonists may still offer a feasible approach for the activation of mGluRs, important progress has been made in the discovery of novel subtype-selective allosteric ligands, including positive allosteric modulators (PAMs) of mGluR2 and mGluR5. These allosteric mGluR ligands have improved properties for clinical development and have served as key preclinical tools for a more in-depth understanding of the potential roles of these different mGluR subtypes for the treatment of schizophrenia.

Keywords

Cognition Dopamine GABA Glutamate Metabotropic glutamate receptor Negative allosteric modulator NMDA receptor Positive allosteric modulator Schizophrenia 

Abbreviations

5-CSRTT

5-Choice serial reaction time task

7TM

7-Transmembrane domain

A-841720

9-Dimethylamino-3-(N-hexamethyleneiminyl)-3H-5-thia-1,3,6-triazafluoren-4-one

AAPA

Active allothetic place avoidance

AC

Adenylyl cyclase

ACPT-I

(1S,3R,4S)-1-Aminocyclopentane-1,3,4-tricarboxylic acid

ADX-47273

S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-methanone

AIDA

(RS)-1-Aminoindan-1,5-dicarboxylic acid

AMPA

α-Amino-3-hydroxyl-5-methyl-4-isoxazole-propionate

AMPAR

α-Amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor

BAY26-7620 BAY 36-7620

(3aS,6aS)-Hexahydro-5-methylene-6a-(2-naphthalenylmethyl)-1H-cyclopenta[c]furan-1-one

BINA

3′-[[(2-Cyclopentyl-2,3-dihydro-6,7-dimethyl-1-oxo-1H-inden-5-yl)oxy]methyl]-[1,1′-biphenyl]-4-carboxylic acid

cAMP

Cyclic adenosine monophosphate

CBiPES

N-(4′-Cyano-[1,1′-biphenyl]-3-yl-N-(3-pyridinylmethyl))-ethanesulfonamide hydrochloride

CDPPB

3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide

CFMTI

2-Cyclopropyl-5-(1-(2-fluoro-3-pyridinyl)-5-methyl-1H-1,2,3-triazol-4-yl)-2,3-dihydro-1H-isoindol-1-one

CGI-S

Clinical global impression—severity score

CPCCOEt

7-(Hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester

CPPZ

1-(4-(2-Chloro-4-fluorophenyl)piperazin-1-yl)-2-(pyridin-4-ylmethoxy)ethanone

CPT

Continuous Performance Test

DAG

Diacyl-glycerol

DCG-IV

(2S,2′R,3′R)-2-(2′,3′-Dicarboxycyclopropyl)glycine

DFB

Desformylflustrabromine hydrochloride

DMTP

Delayed matching-to-position task

DOB

2,5-Dimethoxy-4-bromoamphetamine

DOI

(±)1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane

EAAC1

Excitatory amino acid carrier 1

EAAT

Excitatory amino acid transporter

EPSP

Excitatory postsynaptic potential

ER

Endoplasmic reticulum

ERK

Extracellular signal-regulated kinase

FTIDC

4-(1-(2-Fluoropyridin-3-yl)-5-methyl-1H-1,2,3,-triazol-4-yl)-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide

GABA

γ-Aminobutyric acid

GKAP

Guanylate kinase-associated protein

GLAST

Glutamate aspartate transporter

GLT-1

Glial glutamate transporter 1

Glu

Glutamate

GPCR

G protein-coupled receptor

GTP

Guanosine triphosphate

IP3

Inositol 1,4,5-triphosphate

JNJ16567083

(3-Ethyl-2-(11 C)methyl-quinolin-6-yl)-(cis-4-methoxycyclohexyl)methanone

JNJ16259685

(3,4-Dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-(cis-4-methoxy cyclohexyl)-methanone

KO

Knockout

LCCG

L-2-(Carboxycyclopropyl)glycine

LCCG-I

(2S,1′S,2′S)-2-(Carboxycyclopropyl)glycine

LSP1-2111

(2 S)-2-Amino-4-[hydroxy[hydroxy(4-hydroxy-3-methoxy-5-nitro-phenyl)methyl]phosphoryl]butanoic acid

LTD

Long-term depression

LTP

Long-term potentiation

LY2140023

(1R,4S,5S,6S)-2-Thiabicyclo[3.1.0]-hexane-4,6-dicarboxylic acid,4-[(2S)-2-amino-4-(methylthio)-1-oxobutyl]amino-, 2,2-dioxide monohydrate

LY314582

(+)-(1S,2S,5R,6S)-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid monohydrate

LY341495

(1S,2S)-2-[(1R)-1-Amino-1-carboxy-2-(2,6-dioxo-3H-purin-9-yl)ethyl]cyclopropane-1-carboxylic acid

LY354740

(1S,2S,5R,6S)-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid

LY366563

2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid

LY367385

2-Methyl-4-carboxyphenylglycine; alpha-methyl-4-carboxyphenylglycine

LY379268

(1S,2R,5R,6R)-2-Amino-4-oxabicyclo[3.1.0]hexane-2,6-dicarboxylic acid

LY404039

(−)-(1R,4S,5S,6S)-4-Amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid

LY418426

(1S,2S,5R,6R)-2-Amino-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid

LY487379

N-(4-(2-Methoxyphenoxy)phenyl)-N-(2,2,2-trifluoroethylsulfonyl)pyrid-3-ylmethylamine

LY544344

(1S,2S,5R,6S)-2-[(2′S)-(2′-Amino)propionyl]aminobicyclo [3.1.0]hexane-2,6-dicarboxylic acid hydrochloride

MAPK

Mitogen-activated protein kinase

mGluR

Metabotropic glutamate receptor

mGluR1a

Splice variant of mGluR1

mGluR5a

Splice variant of mGluR5

mGluR5b

Splice variant of mGluR5

MGS0008

5-[2-[4-(6-Fluoro-1H-indole-3-yl) piperidin-1-yl]ethyl]-4-(4-fluorophenyl)thiazole-2-carboxylic acid amide

MGS0028

(1R, 2S, 5S, 6S)-2-Amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid monohydrate

MGS0039

(1R,2R,3R,5R,6R)-2-Amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid

MK-801

(5S,10R)-(+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-imine maleate

MPEP

6-Methyl-2-(phenylethynyl)-pyridin

MTEP

3-((2-Methyl-4-thiazolyl)ethynyl)pyridine

NAM

Negative allosteric modulator

NMDA

N-methyl-d-aspartate

NMDAR

N-methyl-d-aspartate receptor

NR1

NMDA receptor subunit 1

PCP

Phencyclidine

PAM

Positive allosteric modulator

PANSS

Positive and negative syndrome scale

PDZ

Postsynaptic density 95, discs large, zona occludens 1 domain

PI3 kinase

Phosphatidylinositol 3-kinase

PIKE-L

PI3 kinase enhancer long form

PIP2

Phosphatidylinositol biphosphate

PKA

Protein kinase A

PKC

Protein kinase C

PP2A

Protein phosphatase 2A

PPI

Prepulse inhibition of the acoustic startle response

PP2C

Protein phosphatase 2 C

PSD-95

Postsynaptic density

(R)-CPP

3-((R)-2-Carboxypiperazin-4-yl)-propyl-1-phosphonic acid

R214127

1-(3,4-Dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-2-phenyl-1- ethanone

Ro 01-6128

Diphenylacetyl-carbamic acid ethyl ester

Ro 67-4853

9H-Xanthen-9-ylcarbonyl-carbamic acid

Ro 67-7476

(2S)-2-(4-Fluorophenyl)-1-[(4-methylphenyl)sulfonyl]-pyrrolidine

SKF-82958

3-Allyl-6-chloro-1-phenyl-1,2,4,5-tetrahydro-3-benzazepine-7,8-diol

TBS

Threshold theta burst stimulation

VFD

Venus fly trap domain

VU29

4-Nitro-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide

VU0092273

(4-Hydroxypiperidin-1-yl)(4-(phenylethynyl)phenyl)methanone

VU0360172

N-Cyclobutyl-6-((3-fluorophenyl)ethynyl)nicotinamide

VU0361747

(6-((3-Fluorophenyl)ethynyl)pyridin-3-yl)(4-hydroxypiperidin-1-yl)methanone

VU0364289

2-(4-(2-(Benzyloxy)acetyl)piperazin-1-yl)benzonitrile

YM298198

6-Amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-a]benzimidazole-2-carboxamide hydrochloride

Notes

Acknowledgments

Beth Herman and Michael Bubser contributed equally to the authorship of this text.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • E. J. Herman
    • 1
    • 2
  • M. Bubser
    • 1
    • 2
  • P. J. Conn
    • 1
    • 2
  • C. K. Jones
    • 1
    • 2
  1. 1.Vanderbilt Center for Neuroscience Drug DiscoveryVanderbilt University Medical CenterNashvilleUSA
  2. 2.Department of PharmacologyVanderbilt University Medical CenterNashvilleUSA

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