New positive allosteric modulators of the metabotropic glutamate receptor 2 (mGluR2). Identification and synthesis of N-propyl-5-substituted isoquinolones

Trabanco, Andrés A.; Duvey, Guillaume; Cid, José M.; Macdonald, Gregor; Cluzeau, Philippe; Nhem, Vanthea; Furnari, Rocco; Behaj, Nadia; Poulain, Géraldine; Finn, Terry; Poli, Sonia; Lavreysen, Hilde; Raux, Alexandre; Thollon, Yves; Poirier, Nicolas; D’Addona, David; Andrés, Juvenal; Lütjens, Robert; Poul, Emmanuel Le; Imogai, Hassan; Rocher, Jean‐Philippe

doi:10.1039/c0md00200c

Cited by 12 publications

(11 citation statements)

References 15 publications

(21 reference statements)

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“…The Ϫlog 10 (EC 50 ) from mGluR2 transfected HEK/TRPC4␤ cells is 4.63 Ϯ 0.12. The potency observed in these experiments is within the previously reported Ϫlog 10 (EC 50 ) range of 4.69 -5.39 for mGluR2 (26), although less potent than reported for responses based on G protein-regulated inwardly rectifying potassium channels (GIRK) and a thallium flux assay, where the Ϫlog 10 (EC 50 ) was found to be 5.1 (27). Similar results were observed for HEK/ Responses from cells were represented in the presence (Ⅺ) or absence (f) of 100 ng/ml pertussis toxin (PTX).…”

Section: L-glutamate And/or L-sop Induced Membrane Potential Change Isupporting

confidence: 69%

Selectivity and Evolutionary Divergence of Metabotropic Glutamate Receptors for Endogenous Ligands and G Proteins Coupled to Phospholipase C or TRP Channels

Kang

Menlove

et al. 2014

Journal of Biological Chemistry

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Section: L-glutamate And/or L-sop Induced Membrane Potential Change Isupporting

confidence: 69%

Selectivity and Evolutionary Divergence of Metabotropic Glutamate Receptors for Endogenous Ligands and G Proteins Coupled to Phospholipase C or TRP Channels

Kang

Menlove

et al. 2014

Journal of Biological Chemistry

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“…These compounds are selective for mGlu 2 receptors and have efficacy in animal models of antipsychotic activity similar to that seen with mGlu 2/3 receptor agonists (Galici et al ., ). The number of reports on mGlu 2 receptor PAM chemical series has increased over recent years (Trabanco et al ., , Trabanco and Cid, ) including multiple lead series from our laboratories (Cid‐Nuñez et al ., 2008b; 2010b; Tresadern et al ., ; Trabanco et al ., 2011c; 2012; Cid et al ., 2012a,b).…”

Section: Introductionmentioning

confidence: 99%

Molecular determinants of positive allosteric modulation of the human metabotropic glutamate receptor 2

Farinha

Lavreysen

Peeters

et al. 2015

British J Pharmacology

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BACKGROUND AND PURPOSEThe activation of the metabotropic glutamate receptor 2 (mGlu2) reduces glutamatergic transmission in brain regions where excess excitatory signalling is implicated in disorders such as anxiety and schizophrenia. Positive allosteric modulators (PAMs) can provide a fine-tuned potentiation of these receptors' function and are being investigated as a novel therapeutic approach. An extensive set of mutant human mGlu2 receptors were used to investigate the molecular determinants that are important for positive allosteric modulation at this receptor. EXPERIMENTAL APPROACHSite-directed mutagenesis, binding and functional assays were employed to identify amino acids important for the activity of nine PAMs. The data from the radioligand binding and mutagenesis studies were used with computational docking to predict a binding mode at an mGlu2 receptor model based on the recent structure of the mGlu1 receptor. KEY RESULTSNew amino acids in TM3 (R635, L639, F643), TM5 (L732) and TM6 (W773, F776) were identified for the first time as playing an important role in the activity of mGlu2 PAMs. CONCLUSIONS AND IMPLICATIONSThis extensive study furthers our understanding of positive allosteric modulation of the mGlu2 receptor and can contribute to improved future design of mGlu2 PAMs. Abbreviations

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“…Both leads demonstrated to have behavioural effects similar to mGlu2/mGlu3 receptor agonists proving efficacy in a wide range of models of psychiatric disorders providing preclinical proof of concept for PAMs [37,40,41,77,78]. 110 J.M. Cid et al…”

Section: N-arylsulfonamidesmentioning

confidence: 95%

“…Relevant SAR information for this chemical series of compounds was later published [108][109][110]. Compounds 45 and 46 ( Fig.…”

Section: Isoquinolonesmentioning

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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New positive allosteric modulators of the metabotropic glutamate receptor 2 (mGluR2). Identification and synthesis of N-propyl-5-substituted isoquinolones

Abstract: N-propyl-5-substituted isoquinolones were identified as mGluR2 PAMs via high-throughput screening (HTS). Initial SAR exploration led to the identification of compound 20.

Cited by 12 publications

References 15 publications

Selectivity and Evolutionary Divergence of Metabotropic Glutamate Receptors for Endogenous Ligands and G Proteins Coupled to Phospholipase C or TRP Channels

Selectivity and Evolutionary Divergence of Metabotropic Glutamate Receptors for Endogenous Ligands and G Proteins Coupled to Phospholipase C or TRP Channels

Molecular determinants of positive allosteric modulation of the human metabotropic glutamate receptor 2

Metabotropic Glutamate Receptor 2 Activators

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