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Metabotropic Glutamate Receptor 2 Activators

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Small Molecule Therapeutics for Schizophrenia

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 13))

Abstract

Schizophrenia is a common and severe, often disabling psychiatric illness of unknown aetiology that affects approximately 24 million people worldwide. The illness is characterized by symptomatology comprising positive symptoms (hallucinations and delusional behaviours), negative symptoms (anhedonia, social withdrawal and apathy) and cognitive dysfunction (diminished capacity for learning, memory and executive function). Current pharmacological treatments are effective at alleviating positive symptoms but have limited impact on negative symptoms and cognitive deficits. Furthermore, the extrapyramidal symptoms, hyperprolactinemia and metabolic syndrome, including substantial weight gain, are typical side effects limiting the value of many of these drugs for patients. Thus, drugs that better serve the patient population by effectively treating all symptoms with improved safety and tolerability remain a critical unmet need. Modulation of the metabotropic glutamate type 2 (mGlu2) receptor has emerged as a promising mechanism for the treatment of CNS diseases, with the potential to provide a new and more effective avenue for the treatment of schizophrenia.

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Abbreviations

Ar:

Aryl

B/P:

Brain-to-plasma ratio

BINA:

Biphenyl indanone A

CF3O:

Trifluoromethoxy

Clp:

Clearance

CNS:

Central nervous system

F%:

% Oral bioavailability

hERG:

Human ether-a-go-go-related gene

HTS:

High-throughput screening

MDD:

Major depressive disorders

MeO:

Methoxy

mGlu:

Metabotropic glutamate

NMDA:

N-methyl-D-aspartate

PAM:

Positive allosteric modulator

PCP:

Phencyclidine

PhO:

Phenoxy

PK:

Pharmacokinetics

REM:

Rapid eye movement

SAR:

Structure–activity relationship

Sw-EEG:

Sleep-wake electroencephalogram

t 1/2 :

Half-life

μ:

Micro

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Authors and Affiliations

  1. Neuroscience Medicinal Chemistry, Janssen Research and Development, Janssen-Cilag S.A., Jarama 75, 45007, Toledo, Spain

    José M. Cid & Andrés A. Trabanco

  2. Neuroscience Biology, Janssen Research and Development, Turnhoutseweg 30, 2340, Beerse, Belgium

    Hilde Lavreysen

Authors
  1. José M. Cid
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  2. Andrés A. Trabanco
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  3. Hilde Lavreysen
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Correspondence to José M. Cid .

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Editors and Affiliations

  1. Reigner, France

    Sylvain Celanire

  2. Addex Therapeutics, Geneva, Switzerland

    Sonia Poli

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Cid, J.M., Trabanco, A.A., Lavreysen, H. (2014). Metabotropic Glutamate Receptor 2 Activators. In: Celanire, S., Poli, S. (eds) Small Molecule Therapeutics for Schizophrenia. Topics in Medicinal Chemistry, vol 13. Springer, Cham. https://doi.org/10.1007/7355_2014_48

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