Metabotropic Glutamate 2/3 Receptor Agonists and Positive Allosteric Modulators of Metabotropic Glutamate Receptor 2 as Novel Agents for the Treatment of Schizophrenia

Marek, Gerard J.; Kinon, Bruce J.; McKinzie, David L.; Schkeryantz, Jeffrey M.; Monn, James A.

doi:10.1002/9781118309421.ch6

Cited by 4 publications

(1 citation statement)

References 157 publications

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“…Thus, shortly after the publication of LY487379, series such as acetophenones [44][45][46][47], indoles [48], 1,5-pyridones [49], 1,4-pyridones [50], isoindolones [51,52], pyrazolones [53], thienopyrimidines [54], oxazolidinones [55,56], benzimidazoles [57][58][59] and oxazolopyrimidones [60], were reported as novel mGlu2 receptor PAM chemotypes. For detailed background information, we refer to the reviews by Sheffler [61], Rudd and McCauley [62], Fraley [63], Marek [64] and Trabanco [65,66], which cover literature and patent applications.…”

Section: Mglu2 Receptor Positive Allosteric Modulatorsmentioning

confidence: 99%

Metabotropic Glutamate Receptor 2 Activators

Cid¹,

Trabanco²,

Lavreysen

2014

Small Molecule Therapeutics for Schizophrenia

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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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Section: Mglu2 Receptor Positive Allosteric Modulatorsmentioning

confidence: 99%

Metabotropic Glutamate Receptor 2 Activators

Cid¹,

Trabanco²,

Lavreysen

2014

Small Molecule Therapeutics for Schizophrenia

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Synthesis and Pharmacological Characterization of C4-Disubstituted Analogs of 1S,2S,5R,6S-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylate: Identification of a Potent, Selective Metabotropic Glutamate Receptor Agonist and Determination of Agonist-Bound Human mGlu2 and mGlu3 Amino Terminal Domain Structures

et al. 2015

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As part of our ongoing research to identify novel agents acting at metabotropic glutamate 2 (mGlu2) and 3 (mGlu3) receptors, we have previously reported the identification of the C4α-methyl analog of mGlu2/3 receptor agonist 1 (LY354740). This molecule, 1S,2S,4R,5R,6S-2-amino-4-methylbicyclo[3.1.0]hexane-2,6-dicarboxylate 2 (LY541850), exhibited an unexpected mGlu2 agonist/mGlu3 antagonist pharmacological profile, whereas the C4β-methyl diastereomer (3) possessed dual mGlu2/3 receptor agonist activity. We have now further explored this structure-activity relationship through the preparation of cyclic and acyclic C4-disubstituted analogs of 1, leading to the identification of C4-spirocyclopropane 5 (LY2934747), a novel, potent, and systemically bioavailable mGlu2/3 receptor agonist which exhibits both antipsychotic and analgesic properties in vivo. In addition, through the combined use of protein-ligand X-ray crystallography employing recombinant human mGlu2/3 receptor amino terminal domains, molecular modeling, and site-directed mutagenesis, a molecular basis for the observed pharmacological profile of compound 2 is proposed.

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mGluR2 positive allosteric modulators: an updated patent review (2013–2018)

Trabanco¹,

Bartolomé²,

Cid³

2019

Expert Opinion on Therapeutic Patents

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Metabotropic Glutamate 2/3 Receptor Agonists and Positive Allosteric Modulators of Metabotropic Glutamate Receptor 2 as Novel Agents for the Treatment of Schizophrenia

Cited by 4 publications

References 157 publications

Metabotropic Glutamate Receptor 2 Activators

Metabotropic Glutamate Receptor 2 Activators

mGluR2 positive allosteric modulators: an updated patent review (2013–2018)

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