"Acamprosate mGluR5 antagonist Human trials e.g., Erickson et al., 2011 Memantine mGluR5 antagonist Human trials e.g., Erickson et al., 2009 AFQ056 mGluR5 antagonist Human trials e.g., Berg et al., 2011 Fenobam mGluR5 antagonist Human trials e.g., Berry-Kravis et al., 2009 Frontiers in Neuroscience | www.frontiersin.org 3 March 2015 antagonists produce side effects in humans that include mem - ory impairment , psychotic episodes , and strokes ( Swanson et al. , 2005 ) . "
[Show abstract][Hide abstract] ABSTRACT: In the present review, we deliver an overview of the involvement of metabotropic glutamate receptor 5 (mGluR5) activity and density in pathological anxiety, mood disorders and addiction. Specifically, we will describe mGluR5 studies in humans that employed Positron Emission Tomography (PET) and combined the findings with preclinical animal research. This combined view of different methodological approaches-from basic neurobiological approaches to human studies-might give a more comprehensive and clinically relevant view of mGluR5 function in mental health than the view on preclinical data alone. We will also review the current research data on mGluR5 along the Research Domain Criteria (RDoC). Firstly, we found evidence of abnormal glutamate activity related to the positive and negative valence systems, which would suggest that antagonistic mGluR5 intervention has prominent anti-addictive, anti-depressive and anxiolytic effects. Secondly, there is evidence that mGluR5 plays an important role in systems for social functioning and the response to social stress. Finally, mGluR5's important role in sleep homeostasis suggests that this glutamate receptor may play an important role in RDoC's arousal and modulatory systems domain. Glutamate was previously mostly investigated in non-human studies, however initial human clinical PET research now also supports the hypothesis that, by mediating brain excitability, neuroplasticity and social cognition, abnormal metabotropic glutamate activity might predispose individuals to a broad range of psychiatric problems.
Frontiers in Neuroscience 03/2015; 9:86. DOI:10.3389/fnins.2015.00086 · 3.66 Impact Factor
"The metabotropic glutamate receptor subtype 5 (mGlu 5 ) has emerged as an exciting new target for treatment of multiple neurological and psychiatric disorders. Selective mGlu 5 negative allosteric modulators (NAMs) are advancing in clinical development for treatment of Fragile X syndrome, Parkinson's disease, and affective disorders (Berg et al, 2011; Emmitte, 2013; Jacquemont et al, 2011) and positive allosteric modulators (PAMs) of mGlu 5 may provide a novel approach to treatment of psychosis and cognitive disturbances in schizophrenia patients (Conn et al, 2011; Noetzel et al, 2012). Advancing mGlu 5 allosteric modulators in early clinical studies has been facilitated by the availability of highly selective positron emission tomography (PET) radioligands that allow unambiguous quantitative assessment of receptor occupancy (RO) in the brain after systemic administration of defined doses of test compounds (Majo et al, 2013; Mu et al, 2010). "
[Show abstract][Hide abstract] ABSTRACT: Allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGlu5) have exciting potential as therapeutic agents for multiple brain disorders. Translational studies with mGlu5 modulators have relied on mGlu5 allosteric site positron emission tomography (PET) radioligands to assess receptor occupancy in the brain. However, recent structural and modeling studies suggest that closely related mGlu5 allosteric modulators can bind to overlapping but not identical sites, which could complicate interpretation of in vivo occupancy data, even when PET ligands and drug leads are developed from the same chemical scaffold. We now report that systemic administration of the novel mGlu5 positive allosteric modulator (PAM) VU0092273 displaced the structurally related mGlu5 PET ligand, [(18)F]FPEB, with measures of in vivo occupancy that closely aligned with its in vivo efficacy. In contrast, a close analog of VU0092273 and [(18)F]FPEB, VU0360172, provided robust efficacy in rodent models in the absence of detectable occupancy. Furthermore, a structurally unrelated mGlu5 negative allosteric modulator (NAM), VU0409106 displayed measures of in vivo occupancy that correlated well with behavioral effects, despite the fact that VU0409106 is structurally unrelated to [(18)F]FPEB. Interestingly, all three compounds inhibit radioligand binding to the prototypical MPEP/FPEB allosteric site in vitro. However, VU0092273 and VU0409106 bind to this site in a fully competitive manner, whereas the interaction of VU0360172 is non-competitive. Thus, while close structural similarity between PET ligands and drug leads does not circumvent issues associated with differential binding to a given target, detailed molecular pharmacology analysis accurately predicts utility of ligand pairs for in vivo occupancy studies.Neuropsychopharmacology accepted article preview online, 22 September 2014. doi:10.1038/npp.2014.245.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 09/2014; 40(3). DOI:10.1038/npp.2014.245 · 7.05 Impact Factor
"iGlu receptors drugs suppressing glutamate excitatory transmission often create undesirable side effects (14), whereas acting on mGlu receptors could lead to a more subtle and/or circuit-selective modulation of excitatory transmission (15). Pharmacologic characterization of metabotropic glutamate 5 (mGlu5) receptors and its selective negative allosteric modulators (NAMs) show therapeutic potential in animal models of PD (16–18) and efficacy in human PD (19, 20). While mGlu5 receptors regulate l-DOPA-induced motor behavior, the mechanisms involved remains to be fully elucidated (21). "
[Show abstract][Hide abstract] ABSTRACT: Anti-glutamatergic drugs can relieve Parkinson's disease (PD) symptoms and decrease l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesias (LID). This review reports relevant studies investigating glutamate receptor subtypes in relation to motor complications in PD patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys. Antagonists of the ionotropic glutamate receptors, such as N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, display antidyskinetic activity in PD patients and animal models such as the MPTP monkey. Metabotropic glutamate 5 (mGlu5) receptor antagonists were shown to reduce the severity of LID in PD patients as well as in already dyskinetic non-human primates and to prevent the development of LID in de novo treatments in non-human primates. An increase in striatal post-synaptic NMDA, AMPA, and mGlu5 receptors is documented in PD patients and MPTP monkeys with LID. This increase can be prevented in MPTP monkeys with the addition of a specific glutamate receptor antagonist to the l-DOPA treatment and also with drugs of various pharmacological specificities suggesting multiple receptor interactions. This is yet to be well documented for presynaptic mGlu4 and mGlu2/3 and offers additional new promising avenues.
Frontiers in Neurology 08/2014; 5:144. DOI:10.3389/fneur.2014.00144
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