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Fabrizio Gasparini - One of the best experts on this subject based on the ideXlab platform.

  • inhibiting mglur5 activity by afq056 Mavoglurant rescues circuit specific functional connectivity in fmr1 knockout mice
    NeuroImage, 2019
    Co-Authors: Fabrizio Gasparini, Valerio Zerbi, Marija Markicevic, Aileen Schroeter, Markus Rudin, Nicole Wenderoth
    Abstract:

    Previous work has demonstrated that neuroimaging biomarkers which capture functional connectivity of the brain can be used to define a specific and robust endophenotype in Fmr1-/y mice, a well-established animal model of human Fragile-X Syndrome (FXS). However, it is currently unknown whether this macroscopic measure of brain connectivity is sufficiently sensitive to reliably detect changes caused by pharmacological interventions. Here we inhibited the activity of the metabotropic glutamate receptor-5 (mGluR5) using AFQ056/Mavoglurant, a drug that is assumed to normalize excitatory/inhibitory neural signaling imbalances in FXS. We employed resting-state-fMRI (rs-fMRI) and diffusion-weighted imaging (DWI) to test whether Mavoglurant re-established brain connectivity - at least partly - within some of the affected circuits in Fmr1-/y mice that are related to social behavior deficits. In line with previous findings, we observed that Fmr1-/y mice exhibited impaired social interaction, reduced connectivity in three main functional networks and altered network topology. At the group level, Mavoglurant did neither rescue abnormal social behavioral nor white matter abnormalities; however, for some, but not all of these circuits Mavoglurant had a genotype-specific effect of restoring functional connectivity. These results show that rs-fMRI connectivity is sufficiently sensitive to pick up system-level changes after the pharmacological inhibition of mGluR5 activity. However, our results also show that the effects of Mavoglurant are confined to specific networks suggesting that behavioral benefits might be restricted to narrow functional domains.

  • Mavoglurant augmentation in ocd patients resistant to selective serotonin reuptake inhibitors a proof of concept randomized placebo controlled phase 2 study
    Advances in Therapy, 2017
    Co-Authors: Daniel Rutrick, Fabrizio Gasparini, Dan J. Stein, Maurizio Fava, Ganesan Subramanian, Brian Smith, Gregor Hasler, Jangho Cha, Toni Donchev, Magdalena Ocwieja
    Abstract:

    Introduction To determine if Mavoglurant (modified release) as an augmentation therapy to selective serotonin reuptake inhibitors (SSRIs) could have beneficial effects reducing Yale–Brown Obsessive Compulsive Scale (Y-BOCS) total score in patients with obsessive–compulsive disorder (OCD) resistant to SSRI treatment.

  • Mavoglurant augmentation in ocd patients resistant to selective serotonin reuptake inhibitors a proof of concept randomized placebo controlled phase 2 study
    Advances in Therapy, 2017
    Co-Authors: Daniel Rutrick, Fabrizio Gasparini, Dan J. Stein, Maurizio Fava, Ganesan Subramanian, Brian Smith, Gregor Hasler, Jangho Cha, Toni Donchev, Magdalena Ocwieja
    Abstract:

    To determine if Mavoglurant (modified release) as an augmentation therapy to selective serotonin reuptake inhibitors (SSRIs) could have beneficial effects reducing Yale–Brown Obsessive Compulsive Scale (Y-BOCS) total score in patients with obsessive–compulsive disorder (OCD) resistant to SSRI treatment. This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 2 study. Patients remained on their SSRI treatment and Mavoglurant or placebo was added on. Non-smoking men and women aged 18–65 years primarily diagnosed with OCD according to Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR) criteria were randomized (1:1) to Mavoglurant or placebo groups. After 50 patients were randomized, an interim analysis was conducted to determine whether the study should be continued. The primary outcome measure was absolute change in Y-BOCS from baseline at week 17. Safety was assessed by recording adverse events (AEs) and serious adverse events (SAEs). Interim analysis led to a decision to terminate the study. In total 38 (76.0%) participants completed 17 weeks of treatment and 37 (74.0%) completed the study. There was no significant difference in least squares (LS) mean change from baseline at week 17 in Y-BOCS total score for Mavoglurant compared with placebo groups [−6.9 (1.75) vs. −8.0 (1.78), respectively; LS mean difference 1.1; 95% CI −3.9, 6.2; p = 0.671]. The incidence of AEs was higher in the Mavoglurant compared with the placebo group (80.8% vs. 70.8%, respectively). This study of Mavoglurant in OCD was terminated because of the lack of efficacy at interim analysis. The study did not support the use of an antagonist of mGluR5 receptors for OCD treatment. The study was registered with ClinicalTrials.gov: NCT01813019. This study was sponsored by Novartis Pharma AG, Basel, Switzerland.

  • a randomized placebo controlled trial of afq056 for the treatment of chorea in huntington s disease
    Movement Disorders, 2015
    Co-Authors: Ralf Reilmann, Marielaure Rouzadedominguez, Nicole Pezous, Carsten Saft, S D Sussmuth, Josef Priller, Anne Elizabeth Rosser, Hugh Rickards, Ludger Schols, Fabrizio Gasparini
    Abstract:

    Background This study investigated the hypothesis that AFQ056 (Mavoglurant), a selective metabotropic glutamate receptor 5 antagonist, reduces chorea in Huntington's disease (HD). Methods This 32-day randomized, double-blind, parallel-group, proof-of-concept study investigated AFQ056 (25-150 mg [incremental doses], twice-daily) versus placebo in patients with HD. Primary efficacy assessments were the chorea-sum score and orientation index (nondominant hand) from the quantitative motor (Q-Motor) grasping task at day 28. Key secondary efficacy assessments included finger-tapping in the Unified Huntington's Disease Rating Scale–Total Motor Score and Q-Motor measures. Safety and tolerability were assessed. Results Overall, 42 patients were randomized. At day 28, no improvement was observed on the primary efficacy assessments (P > 0.10) with AFQ056 versus placebo. The Q-Motor speeded-tapping interonset interval variability was reduced with AFQ056 versus placebo for the nondominant hand (P = 0.01). The incidence of adverse events was 66.7% with AFQ056 and 57.1% with placebo. Conclusions AFQ056 did not reduce choreatic movements in HD, but was well tolerated. The clinical relevance of the Q-Motor findings (speeded-tapping) are unknown and may warrant further investigation. © 2015 International Parkinson and Movement Disorder Society

  • afq056 Mavoglurant a novel clinically effective mglur5 antagonist identification sar and pharmacological characterization
    Bioorganic & Medicinal Chemistry, 2014
    Co-Authors: Ivo Vranesic, Silvio Ofner, Peter J Flor, Graeme Bilbe, Rochdi Bouhelal, Albert Enz, Sandrine Desrayaud, Kevin H Mcallister, Rainer Kuhn, Fabrizio Gasparini
    Abstract:

    Here we describe the identification, structure-activity relationship and the initial pharmacological characterization of AFQ056/Mavoglurant, a structurally novel, non-competitive mGlu5 receptor antagonist. AFQ056/Mavoglurant was identified by chemical derivatization of a lead compound discovered in a HTS campaign. In vitro, AFQ056/Mavoglurant had an IC50 of 30 nM in a functional assay with human mGluR5 and was selective over the other mGluR subtypes, iGluRs and a panel of 238 CNS relevant receptors, transporter or enzymes. In vivo, AFQ056/Mavoglurant showed an improved pharmacokinetic profile in rat and efficacy in the stress-induced hyperthermia test in mice as compared to the prototypic mGluR5 antagonist MPEP. The efficacy of AFQ056/Mavoglurant in humans has been assessed in L-dopa induced dyskinesia in Parkinson's disease and Fragile X syndrome in proof of principle clinical studies.

Magdalena Ocwieja - One of the best experts on this subject based on the ideXlab platform.

  • Mavoglurant augmentation in ocd patients resistant to selective serotonin reuptake inhibitors a proof of concept randomized placebo controlled phase 2 study
    Advances in Therapy, 2017
    Co-Authors: Daniel Rutrick, Fabrizio Gasparini, Dan J. Stein, Maurizio Fava, Ganesan Subramanian, Brian Smith, Gregor Hasler, Jangho Cha, Toni Donchev, Magdalena Ocwieja
    Abstract:

    Introduction To determine if Mavoglurant (modified release) as an augmentation therapy to selective serotonin reuptake inhibitors (SSRIs) could have beneficial effects reducing Yale–Brown Obsessive Compulsive Scale (Y-BOCS) total score in patients with obsessive–compulsive disorder (OCD) resistant to SSRI treatment.

  • Mavoglurant augmentation in ocd patients resistant to selective serotonin reuptake inhibitors a proof of concept randomized placebo controlled phase 2 study
    Advances in Therapy, 2017
    Co-Authors: Daniel Rutrick, Fabrizio Gasparini, Dan J. Stein, Maurizio Fava, Ganesan Subramanian, Brian Smith, Gregor Hasler, Jangho Cha, Toni Donchev, Magdalena Ocwieja
    Abstract:

    To determine if Mavoglurant (modified release) as an augmentation therapy to selective serotonin reuptake inhibitors (SSRIs) could have beneficial effects reducing Yale–Brown Obsessive Compulsive Scale (Y-BOCS) total score in patients with obsessive–compulsive disorder (OCD) resistant to SSRI treatment. This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 2 study. Patients remained on their SSRI treatment and Mavoglurant or placebo was added on. Non-smoking men and women aged 18–65 years primarily diagnosed with OCD according to Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR) criteria were randomized (1:1) to Mavoglurant or placebo groups. After 50 patients were randomized, an interim analysis was conducted to determine whether the study should be continued. The primary outcome measure was absolute change in Y-BOCS from baseline at week 17. Safety was assessed by recording adverse events (AEs) and serious adverse events (SAEs). Interim analysis led to a decision to terminate the study. In total 38 (76.0%) participants completed 17 weeks of treatment and 37 (74.0%) completed the study. There was no significant difference in least squares (LS) mean change from baseline at week 17 in Y-BOCS total score for Mavoglurant compared with placebo groups [−6.9 (1.75) vs. −8.0 (1.78), respectively; LS mean difference 1.1; 95% CI −3.9, 6.2; p = 0.671]. The incidence of AEs was higher in the Mavoglurant compared with the placebo group (80.8% vs. 70.8%, respectively). This study of Mavoglurant in OCD was terminated because of the lack of efficacy at interim analysis. The study did not support the use of an antagonist of mGluR5 receptors for OCD treatment. The study was registered with ClinicalTrials.gov: NCT01813019. This study was sponsored by Novartis Pharma AG, Basel, Switzerland.

  • metabolism and disposition of the metabotropic glutamate receptor 5 antagonist mglur5 Mavoglurant afq056 in healthy subjects
    Drug Metabolism and Disposition, 2013
    Co-Authors: Markus Walles, Luc Alexis Leuthold, Thierry Wolf, Yi Jin, Michael Ritzau, Joel Krauser, Hanspeter Gschwind, David Carcache, Matthias Kittelmann, Magdalena Ocwieja
    Abstract:

    The disposition and biotransformation of 14C-radiolabeled Mavoglurant were investigated in four healthy male subjects after a single oral dose of 200 mg. Blood, plasma, urine, and feces collected over 7 days were analyzed for total radioactivity, Mavoglurant was quantified in plasma by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), and metabolite profiles were generated in plasma and excreta by high-performance liquid chromatography (HPLC) and radioactivity detection. The chemical structures of Mavoglurant metabolites were characterized by LC-MS/MS, wet-chemical and enzymatic methods, NMR spectroscopy, and comparison with reference compounds. Mavoglurant was safe and well tolerated in this study population. Mavoglurant absorption was ≥50% of dose reaching mean plasma Cmax values of 140 ng/ml (Mavoglurant) and 855 ng-eq/ml (total radioactivity) at 2.5 and 3.6 hours, respectively. Thereafter, Mavoglurant and total radioactivity concentrations declined with mean apparent half-lives of 12 and 18 hours, respectively. The elimination of Mavoglurant occurred predominantly by oxidative metabolism involving primarily 1) oxidation of the tolyl-methyl group to a benzyl-alcohol metabolite (M7) and subsequently to a benzoic acid metabolite (M6), and 2) oxidation of the phenyl-ring leading to a hydroxylated metabolite (M3). The subjects were mainly exposed to Mavoglurant and seven main metabolites, which combined accounted for 60% of 14C-AUC0–72 h (area under the concentration-time curve from time 0 to infinity). The primary steps of Mavoglurant metabolism observed in vivo could partially be reproduced in vitro in incubations with human liver microsomes and recombinant cytochrome P450 enzymes. After 7 days, the mean balance of total radioactivity excretion was almost complete (95.3% of dose) with 36.7% recovered in urine and 58.6% in feces.

Ben Tehan - One of the best experts on this subject based on the ideXlab platform.

  • structure of class c gpcr metabotropic glutamate receptor 5 transmembrane domain
    Nature, 2014
    Co-Authors: A S Dore, K Okrasa, Maria Josefa Serranovega, Robert M Cooke, J C Errey, K. A. Bennett, Samir Khan, J C Patel, Allahyar Jazayeri, Ben Tehan
    Abstract:

    Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate. Structural studies have been restricted to the amino-terminal extracellular domain, providing little understanding of the membrane-spanning signal transduction domain. Metabotropic glutamate receptor 5 is of considerable interest as a drug target in the treatment of fragile X syndrome, autism, depression, anxiety, addiction and movement disorders. Here we report the crystal structure of the transmembrane domain of the human receptor in complex with the negative allosteric modulator, Mavoglurant. The structure provides detailed insight into the architecture of the transmembrane domain of class C receptors including the precise location of the allosteric binding site within the transmembrane domain and key micro-switches which regulate receptor signalling. This structure also provides a model for all class C G-protein-coupled receptors and may aid in the design of new small-molecule drugs for the treatment of brain disorders. An X-ray structure is presented for metabotropic glutamate receptor 5, a class C G-protein-coupled glutamate receptor linked to fragile X syndrome and neurological disorders; this study provides insights into the protein’s mechanism of action. This manuscript presents the X-ray crystal structure of the transmembrane portion of the metabotropic glutamate receptor 5 (mGlu5), a class C G-protein-coupled receptor (GPCR), in the presence of Mavoglurant, a negative allosteric modulator. Negative allosteric modulators of mGlu5 are in clinical trials for the treatment of fragile X syndrome, depression, anxiety, migraine and dyskinesias; positive allosteric modulators of mGlu5 might be useful for the treatment of schizophrenia and cognitive disorders. In this structure, Mavoglurant is found in a pocket that is about 8 A from the extracellular receptor surface.

  • structure of class c gpcr metabotropic glutamate receptor 5 transmembrane domain
    Nature, 2014
    Co-Authors: A S Dore, K Okrasa, Maria Josefa Serranovega, Robert M Cooke, J C Errey, K. A. Bennett, J C Patel, Ali Jazayeri, Samir A Khan, Ben Tehan
    Abstract:

    Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate. Structural studies have been restricted to the amino-terminal extracellular domain, providing little understanding of the membrane-spanning signal transduction domain. Metabotropic glutamate receptor 5 is of considerable interest as a drug target in the treatment of fragile X syndrome, autism, depression, anxiety, addiction and movement disorders. Here we report the crystal structure of the transmembrane domain of the human receptor in complex with the negative allosteric modulator, Mavoglurant. The structure provides detailed insight into the architecture of the transmembrane domain of class C receptors including the precise location of the allosteric binding site within the transmembrane domain and key micro-switches which regulate receptor signalling. This structure also provides a model for all class C G-protein-coupled receptors and may aid in the design of new small-molecule drugs for the treatment of brain disorders.

A S Dore - One of the best experts on this subject based on the ideXlab platform.

  • structure based optimization strategies for g protein coupled receptor gpcr allosteric modulators a case study from analyses of new metabotropic glutamate receptor 5 mglu5 x ray structures
    Journal of Medicinal Chemistry, 2018
    Co-Authors: John A Christopher, A S Dore, K Okrasa, J C Errey, Zoltan Orgovan, Miles Congreve, Fiona H Marshall, Jonathan S Mason, Prakash Rucktooa, Maria Josefa Serranovega
    Abstract:

    Two interesting new X-ray structures of negative allosteric modulator (NAM) ligands for the mGlu5 receptor, M-MPEP (3) and fenobam (4), are reported. The new structures show how the binding of the ligands induces different receptor water channel conformations to previously published structures. The structure of fenobam, where a urea replaces the acetylenic linker in M-MPEP and Mavoglurant, reveals a binding mode where the ligand is rotated by 180° compared to a previously proposed docking model. The need for multiple ligand structures for accurate GPCR structure-based drug design is demonstrated by the different growing vectors identified for the head groups of M-MPEP and Mavoglurant and by the unexpected water-mediated receptor interactions of a new chemotype represented by fenobam. The implications of the new structures for ligand design are discussed, with extensive analysis of the energetics of the water networks of both pseudoapo and bound structures providing a new design strategy for allosteric mod...

  • structure of class c gpcr metabotropic glutamate receptor 5 transmembrane domain
    Nature, 2014
    Co-Authors: A S Dore, K Okrasa, Maria Josefa Serranovega, Robert M Cooke, J C Errey, K. A. Bennett, Samir Khan, J C Patel, Allahyar Jazayeri, Ben Tehan
    Abstract:

    Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate. Structural studies have been restricted to the amino-terminal extracellular domain, providing little understanding of the membrane-spanning signal transduction domain. Metabotropic glutamate receptor 5 is of considerable interest as a drug target in the treatment of fragile X syndrome, autism, depression, anxiety, addiction and movement disorders. Here we report the crystal structure of the transmembrane domain of the human receptor in complex with the negative allosteric modulator, Mavoglurant. The structure provides detailed insight into the architecture of the transmembrane domain of class C receptors including the precise location of the allosteric binding site within the transmembrane domain and key micro-switches which regulate receptor signalling. This structure also provides a model for all class C G-protein-coupled receptors and may aid in the design of new small-molecule drugs for the treatment of brain disorders. An X-ray structure is presented for metabotropic glutamate receptor 5, a class C G-protein-coupled glutamate receptor linked to fragile X syndrome and neurological disorders; this study provides insights into the protein’s mechanism of action. This manuscript presents the X-ray crystal structure of the transmembrane portion of the metabotropic glutamate receptor 5 (mGlu5), a class C G-protein-coupled receptor (GPCR), in the presence of Mavoglurant, a negative allosteric modulator. Negative allosteric modulators of mGlu5 are in clinical trials for the treatment of fragile X syndrome, depression, anxiety, migraine and dyskinesias; positive allosteric modulators of mGlu5 might be useful for the treatment of schizophrenia and cognitive disorders. In this structure, Mavoglurant is found in a pocket that is about 8 A from the extracellular receptor surface.

  • structure of class c gpcr metabotropic glutamate receptor 5 transmembrane domain
    Nature, 2014
    Co-Authors: A S Dore, K Okrasa, Maria Josefa Serranovega, Robert M Cooke, J C Errey, K. A. Bennett, J C Patel, Ali Jazayeri, Samir A Khan, Ben Tehan
    Abstract:

    Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate. Structural studies have been restricted to the amino-terminal extracellular domain, providing little understanding of the membrane-spanning signal transduction domain. Metabotropic glutamate receptor 5 is of considerable interest as a drug target in the treatment of fragile X syndrome, autism, depression, anxiety, addiction and movement disorders. Here we report the crystal structure of the transmembrane domain of the human receptor in complex with the negative allosteric modulator, Mavoglurant. The structure provides detailed insight into the architecture of the transmembrane domain of class C receptors including the precise location of the allosteric binding site within the transmembrane domain and key micro-switches which regulate receptor signalling. This structure also provides a model for all class C G-protein-coupled receptors and may aid in the design of new small-molecule drugs for the treatment of brain disorders.

Baltazar Gomezmancilla - One of the best experts on this subject based on the ideXlab platform.

  • use of metabotropic glutamate 5 receptor antagonists for treatment of levodopa induced dyskinesias
    Parkinsonism & Related Disorders, 2014
    Co-Authors: Olivier Rascol, Baltazar Gomezmancilla, Fabrizio Gasparini, Christopher Kenney, Susan H Fox, Therese Di Paolo
    Abstract:

    Abstract Background Modulation of metabotropic glutamate receptors may be a novel therapeutic approach to manage l -Dopa-induced dyskinesias in patients with Parkinson's disease. This article reviews the rationale for use of metabotropic glutamate 5-receptor antagonists in experimental and clinical l -Dopa-induced dyskinesias. Methods Systematic literature searches were performed (between May 2012–March 2014) for relevant English language articles using PubMed. Additional articles of interest were identified from reference lists of included publications. Relevant clinical abstracts from Movement Disorder Society meetings were included. Results 16 preclinical studies of metabotropic glutamate 5-receptor antagonists in animal models of l -Dopa-induced dyskinesias and 7 clinical studies in patients with Parkinson's disease and l -Dopa-induced dyskinesias were included. Anti-dyskinetic effects of metabotropic glutamate 5-receptor blockade (MPEP, MTEP, fenobam, or MRZ-8676) were reported in dyskinetic 6-hydroxydopamine-lesioned rats. Studies in MPTP-lesioned non-human primates reported anti-dyskinetic effects of MPEP, MTEP, fenobam and Mavoglurant (AFQ056). Three randomized, double-blind clinical trials reported anti-dyskinetic efficacy of Mavoglurant, without effects on anti-parkinsonian therapy, with dizziness the most common adverse event. However, two further studies failed to demonstrate significant anti-dyskinetic efficacy. A randomized, double-blind, placebo-controlled safety study of dipraglurant (ADX48621) demonstrated tolerability and positive exploratory secondary outcomes of reduced dyskinesia. Conclusions Animal model studies provide evidence for anti-dyskinetic efficacy of metabotropic glutamate 5-receptor antagonists. Initial proof-of-concept clinical trials of Mavoglurant and dipraglurant showed positive results; anti-dyskinetic efficacy was not supported by two recent Mavoglurant trials. Further evaluations of optimal dosage and long-term efficacy and safety of metabotropic glutamate 5-receptor antagonists for management of l -Dopa-induced dyskinesias in Parkinson's disease are required.

  • development of Mavoglurant and its potential for the treatment of fragile x syndrome
    Expert Opinion on Investigational Drugs, 2014
    Co-Authors: Baltazar Gomezmancilla, George Apostol, Fabrizio Gasparini, Florian Von Raison, Elizabeth Berrykravis, Mike Ufer, Randi J Hagerman, Sébastien Jacquemont
    Abstract:

    Introduction: Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. With no curative treatment available, current therapeutic approaches are aimed at symptom management. FXS is caused by silencing the FMR1 gene, which encodes FMRP; as loss of FMRP leads to the development of symptoms associated with FXS. Areas covered: In this evaluation, the authors examine the role of the metabotropic glutamate receptor 5 (mGluR5) in the pathophysiology of FXS, and its suitability as a target for rescuing the disease state. Furthermore, the authors review the evidence from preclinical studies of pharmacological interventions targeting mGluR5 in FXS. Lastly, the authors assess the findings from clinical studies in FXS, in particular the use of the Aberrant Behavior Checklist-Community Edition (ABC-C) and the recently developed ABC-C for FXS scale, as clinical endpoints to assess disease modification in this patient population. Expert opinion: There is cautious optimism for the successful...

  • chronic administration of afq056 Mavoglurant restores social behaviour in fmr1 knockout mice
    Behavioural Brain Research, 2013
    Co-Authors: Ilse Gantois, Celine De Esch, Tine Pooters, Baltazar Gomezmancilla, Fabrizio Gasparini, Rudi Dhooge, Ronald A M Buijsen, Ben A Oostra, Rob Willemsen
    Abstract:

    Fragile X syndrome is caused by lack of FMR1 protein (FMRP) leading to severe symptoms, including intellectual disability, hyperactivity and autistic-like behaviour. FMRP is an RNA binding protein involved in the regulation of translation of specific target mRNAs upon stimulation of metabotropic glutamate receptor 5 (mGluR5) at the synapse. The absence of FMRP leads to enhanced activity of mGluR5 signal transduction pathways. Many conflicting results have been reported regarding social behaviour deficits in Fmr1 knockout mice, and little is known about the involvement of mGluR5 pathways on social behaviour.In this study, a three-chambered task was used to determine sociability and preference for social novelty in Fmr1 knockout mice. Disruption of Fmr1 functioning resulted in enhanced interaction with stranger mouse during sociability while no significant changes were observed during preference for social novelty assay. Chronic administration of a specific mGluR5 antagonist, AFQ056/Mavoglurant, was able to restore sociability behaviour of Fmr1 knockout mice to levels of wild type littermates.These results support the importance of mGluR5 signalling pathways on social interaction behaviour and that AFQ056/Mavoglurant might be useful as potential therapeutic intervention to rescue various behavioural aspects of the fragile X phenotype. © 2012 .