Metabotropic Glutamate Receptors for New Treatments in Schizophrenia

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


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.


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



5-Choice serial reaction time task


7-Transmembrane domain




Active allothetic place avoidance


Adenylyl cyclase


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




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




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

BAY26-7620 BAY 36-7620



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


Cyclic adenosine monophosphate


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






Clinical global impression—severity score


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




Continuous Performance Test






Desformylflustrabromine hydrochloride


Delayed matching-to-position task






Excitatory amino acid carrier 1


Excitatory amino acid transporter


Excitatory postsynaptic potential


Endoplasmic reticulum


Extracellular signal-regulated kinase




γ-Aminobutyric acid


Guanylate kinase-associated protein


Glutamate aspartate transporter


Glial glutamate transporter 1




G protein-coupled receptor


Guanosine triphosphate


Inositol 1,4,5-triphosphate


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


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








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


Long-term depression


Long-term potentiation


(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


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


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


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


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


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


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


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


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




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


Mitogen-activated protein kinase


Metabotropic glutamate receptor


Splice variant of mGluR1


Splice variant of mGluR5


Splice variant of mGluR5


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


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


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


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






Negative allosteric modulator




N-methyl-d-aspartate receptor


NMDA receptor subunit 1




Positive allosteric modulator


Positive and negative syndrome scale


Postsynaptic density 95, discs large, zona occludens 1 domain

PI3 kinase

Phosphatidylinositol 3-kinase


PI3 kinase enhancer long form


Phosphatidylinositol biphosphate


Protein kinase A


Protein kinase C


Protein phosphatase 2A


Prepulse inhibition of the acoustic startle response


Protein phosphatase 2 C


Postsynaptic density


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


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





Threshold theta burst stimulation


Venus fly trap domain












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



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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