New positive allosteric modulators of the metabotropic glutamate receptor 2 (mGluR2): Identification and synthesis of N-propyl-8-chloro-6-substituted isoquinolones

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

doi:10.1016/j.bmcl.2010.12.048

Cited by 19 publications

(22 citation statements)

References 11 publications

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“…Materials JNJ-35814376 (Imogai et al, 2006;, JNJ-40068782 (Imogai et al, 2007;Cid-Nuñez et al, 2008a;Lavreysen et al, 2013), JNJ-40297036 (Trabanco et al, 2011b), JNJ-41482012 (Trabanco-Suárez et al, 2009;Tresadern et al, 2010), JNJ-42329001 (Cid-Nuñez et al, 2010a) and JNJ-46281222 (Cid-Nuñez et al, 2010a) are original products of Janssen Research and Development, a division of Janssen Pharmaceutica. LY487379, BINA and LY2607540 (Johnson et al, 2003;Bonnefous et al, 2005;Fell et al, 2011, respectively) were synthesized for in-house use as reference compounds.…”

Section: Amino Acid Selection For Site-directed Mutagenesismentioning

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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Section: Amino Acid Selection For Site-directed Mutagenesismentioning

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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“…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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“…The symptomatic and neuroprotective properties of group III mGluRs agonists are prevented in mGluR 4 knockout mice, which suggest that the modulation of mGluR 4 has the potential to exert antiparkinsonian activity in animal models. Overall, the pharmacological activation with mGluR 2 /mGluR 3 [175][176][177][178][179][180] and mGluR 4 [181][182][183][184][185][186] with agonists and positive allosteric modulators may offer an alternative approach for PD therapeutics.…”

Section: Metabotropic Glutamate Receptorsmentioning

confidence: 99%

Computer-Aided Drug Design Approaches to Study Key Therapeutic Targets in Alzheimer’s Disease

et al. 2017

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Parkinson's Disease (PD) is a long-term neurodegenative brain disorder that mainly affects the motor system. The causes are still unknown, and even though currently there is no cure, several therapeutic options are available to manage its symptoms. The development of novel anti-parkinsonian agents and an understanding of their proper and optimal use are, indeed, highly demanding. For the last decades, L-3,4-DihydrOxyPhenylAlanine or levodopa (L-DOPA) has been the gold-standard therapy for the symptomatic treatment of motor dysfunctions associated to PD. However, the development of dyskinesias and motor fluctuations (wearing-off and on-off phenomena) associated to long-term L-DOPA replacement therapy have limited its antiparkinsonian efficacy. The investigation for non-dopaminergic therapies has been largely explored as an attempt to counteract the motor side effects associated to dopamine replacement therapy. Being one of the largest cell membrane protein families, G-Protein-Coupled Receptors (GPCRs) have become a relevant target for drug discovery focused in a wide range of therapeutic areas, including Central Nervous System (CNS) diseases. The modulation of specific GPCRs potentially implicated in PD, excluding dopamine receptors, may provide promising non-dopaminergic therapeutic alternatives for symptomatic treatment of PD. In this review, we focused on the impact of specific GPCR subclasses, including dopamine receptors, adenosine receptors, muscarinic acetylcholine receptors, metabotropic glutamate receptors, and 5-hydroxytryptamine receptors, on the pathophysiology of PD and the importance of structure-and ligand-based in silico approaches for the development of small molecules to target these receptors.

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New positive allosteric modulators of the metabotropic glutamate receptor 2 (mGluR2): Identification and synthesis of N-propyl-8-chloro-6-substituted isoquinolones

Cited by 19 publications

References 11 publications

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

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

Metabotropic Glutamate Receptor 2 Activators

Computer-Aided Drug Design Approaches to Study Key Therapeutic Targets in Alzheimer’s Disease

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