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mGluR1 Negative Allosteric Modulators: An Alternative Metabotropic Approach for the Treatment of Schizophrenia

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Glutamate-based Therapies for Psychiatric Disorders

Part of the book series: Milestones in Drug Therapy ((MDT))

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Abstract

The potential utility of mGluR1 negative allosteric modulators (NAMs) for treatment of schizophrenia is based on the pharmacological effects of mGluR1 NAMs in animal models for schizophrenia. An mGluR1 NAM antagonized hyperlocomotion and the deficit in prepulse inhibition (PPI) in rodents caused by an indirect dopamine (DA) agonist, methamphetamine as well as by a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, ketamine. In addition, an mGluR1 NAM reversed reduced social interaction by dizocilpine (MK-801) in rats. The antipsychotic-like effects of mGluR1 NAMs are similar to those of the atypical antipsychotic, clozapine, but not of the typical antipsychotic, haloperidol, based on behavioral changes as well as distribution of c-fos expression after the treatment. The similarities and differences between mGluR1 NAMs and mGluR2/3 agonists are discussed.

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Abbreviations

5-HT:

Serotonin

AIDA:

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

BAY36-7620:

(3aS,6aS)-6a-naphtalan-2-ylmethyl-5-methyliden-hexahydro-cyclopental[c]furan-1-on

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

CNS:

Central nervous system

CPCCOEt:

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

DA:

Dopamine

DHPG:

3,5-dihydroxyphenylglycine

dlSTR:

dorsolateral striatum

EMQMCM:

(3-ethyl-2-methyl-quinolin-6-yl)(4-methoxy-cyclohexyl)methanone methansulfonate

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

iGluR:

ionotropic glutamate receptor

JNJ16259685:

(3,4-dihydro-2H-pyrano[2,3]b quinolin-7-yl) (cis-4-methoxycyclohexyl) methanone

LY354740:

(1S,2S,5R,6S)-2-aminobicyclo[3.1.0] hexane-2,6-dicarboxylate monohydrate

LY367385:

(+)-2-methyl-4-carboxyphenylglycine

LY379268:

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

LY456236:

(4-methoxy-phenyl)-(6-methoxy-quinazolin-4-yl)-amine, HCl

MAP:

Methamphetamine

mGluR:

metabotropic glutamate receptor

MK-801:

(5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate

MPEP:

2-methyl-6-(phenylethynyl)pyridine

mPFC:

medial prefrontal cortex

MTEP:

3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine

NAC:

Nucleus accumbens

NAM:

Negative allosteric modulator

NMDA:

N-methyl-d-aspartate

PCP:

Phencyclidine

PFC:

Prefrontal cortex

PPI:

Prepulse inhibition

VTA:

Ventrotegmental area

YM-230888:

N-cycloheptyl-6-({[(2R)-tetrahydrofuran-2-ylmethyl]amino}methyl)thieno[2,3-d]pyrimidin-4-amine

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Acknowledgments

We thank Satoru Itoh, Hirohiko Hikichi, Shunsuke Maehara, Toshifumi Kimura, and Akio Satow who conducted studies with FTIDC and CFMTI.

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Authors and Affiliations

  1. Research and Development Center, Sato Pharmaceutical Co., Ltd, 6-8-5 Higashi-ohi, Shinagawa, Tokyo, 140-0011, Japan

    Hisashi Ohta

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  1. Hisashi Ohta
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  2. Hiroshi Kawamoto
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  3. Gentaroh Suzuki
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Corresponding author

Correspondence to Hisashi Ohta .

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  1. Div Pharmacotherapies & Medical Conseque, National Institute on Drug Abuse, Executive Boulevard 6001, Rockville, 20852, Maryland, USA

    Phil Skolnick

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Ohta, H., Kawamoto, H., Suzuki, G. (2010). mGluR1 Negative Allosteric Modulators: An Alternative Metabotropic Approach for the Treatment of Schizophrenia. In: Skolnick, P. (eds) Glutamate-based Therapies for Psychiatric Disorders. Milestones in Drug Therapy. Birkhäuser, Basel. https://doi.org/10.1007/978-3-0346-0241-9_7

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