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

Trabanco, Andrés A.; Bartolomé, José M.; Cid, José M.

doi:10.1080/13543776.2019.1637421

Cited by 24 publications

(18 citation statements)

References 42 publications

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“…Notably, positive allosteric modulators (PAM) continue to be an active field of research due to its fewer adverse effects, higher selectivity and greater structural diversity compared with orthosteric ligands (Engers and Lindsley, 2013). Two mGlu 2 receptor PAMs have already advanced into schizophrenia and smoking cessation clinical trials (Trabanco et al, 2019). It was shown that activation of mGlu 3 receptor is required for the neuroprotective effects of mGlu 2/3 receptors agonists toward NMDA neurotoxicity in mixed cultures of astrocytes and neurons, whereas enhancers of mGlu 2 receptor may amplify neuronal death (Corti et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

LY354740 Reduces Extracellular Glutamate Concentration, Inhibits Phosphorylation of Fyn/NMDARs, and Expression of PLK2/pS129 α-Synuclein in Mice Treated With Acute or Sub-Acute MPTP

et al. 2020

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Glutamate overactivity in basal ganglia critically contributes to the exacerbation of dopaminergic neuron degeneration in Parkinson's disease (PD). Activation of group II metabotropic glutamate receptors (mGlu 2/3 receptors), which can decrease excitatory glutamate neurotransmission, provides an opportunity to slow down the degeneration of the dopaminergic system. However, the roles of mGlu 2/3 receptors in relation to PD pathology were partially recognized. By using mGlu 2/3 receptors agonist (LY354740) and mGlu 2/3 receptors antagonist (LY341495) in mice challenged with different cumulative doses of 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), we demonstrated that systemic injection of LY354740 reduced the level of extracellular glutamate and the extent of nigro-striatal degeneration in both acute and sub-acute MPTP mice, while LY341495 amplified the lesions in sub-acute MPTP mice only. LY354740 treatment improved behavioral dysfunctions mainly in acute MPTP mice and LY341495 treatment seemed to aggravate motor deficits in subacute MPTP mice. In addition, ligands of mGlu 2/3 receptors also influenced the total amount of glutamate and dopamine in brain tissue. Interestingly, compared with normal mice, MPTPtreated mice abnormally up-regulated the expression of polo-like kinase 2 (PLK2)/pS129 asynuclein and phosphorylation of Fyn/N-methyl-D-aspartate receptor subunit 2A/2B (GluN2A/2B). Both acute and sub-acute MPTP mice treated with LY354740 dosedependently reduced all the above abnormal expression. Compared with MPTP mice treated with vehicle, mice pretreated with LY341495 exhibited much higher expression of p-Fyn Tyr416/p-GluN2B Tyr1472 and PLK2/pS129 a-synuclein in sub-acute MPTP mice models. Thus, our current data indicated that mGlu 2/3 receptors ligands could influence MPTP-induced toxicity, which supported a role for mGlu 2/3 receptors in PD pathogenesis.

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Section: Discussionmentioning

confidence: 99%

LY354740 Reduces Extracellular Glutamate Concentration, Inhibits Phosphorylation of Fyn/NMDARs, and Expression of PLK2/pS129 α-Synuclein in Mice Treated With Acute or Sub-Acute MPTP

et al. 2020

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“…These observations led to hypothesize that modulators of the mGlu2/3-5-HT2A receptors interaction could provide new therapeutic approaches for the management of schizophrenia [40,55,65,66]. According to the hypothesis, mGlu2/3 receptor agonists, or even better mGlu2/3 positive allosteric modulators (PAMs), were analyzed for the cure of psychiatric illness and still represent promising approaches, as recently reviewed by Ferdinando Nicoletti and colleagues [67], despite the heterogeneity of the results from preclinical studies and the negative results of some of the clinical studies carried out so far (reviewed by [68], but see also [69]).…”

Section: F O R P U B L I C a T I O Nmentioning

confidence: 99%

Serotonergic metamodulation of mGlu23 receptors, a new mechanism for pain management: the case of trazodone

Garrone¹,

Olivero²,

Milanese³

et al. 2022

Pharm Adv

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“…The combination of NMDA hypofunction and presynaptic dopamine dysfunction can provide a very good explanation for most clinical aspects of SZ [27]. Further support for the glutamatergic hypothesis of SZ is supplied by the investigated possibility to use ligands of metabotropic glutamate receptors (mGluRs) [28,29], in particular their positive allosteric modulators [30] to alleviate SZ symptoms.…”

Section: Disturbances In Neurotransmission In Szmentioning

confidence: 99%

In Vitro and In Vivo Models for the Investigation of Potential Drugs Against Schizophrenia

et al. 2020

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Schizophrenia (SZ) is a complex psychiatric disorder characterized by positive, negative, and cognitive symptoms, and is not satisfactorily treated by current antipsychotics. Progress in understanding the basic pathomechanism of the disease has been hampered by the lack of appropriate models. In order to develop modern drugs against SZ, efficient methods to study them in in vitro and in vivo models of this disease are required. In this review a short presentation of current hypotheses and concepts of SZ is followed by a description of current progress in the field of SZ experimental models. A critical discussion of advantages and limitations of in vitro models and pharmacological, genetic, and neurodevelopmental in vivo models for positive, negative, and cognitive symptoms of the disease is provided. In particular, this review concerns the important issue of how cellular and animal systems can help to meet the challenges of modeling the disease, which fully manifests only in humans, as experimental studies of SZ in humans are limited. Next, it is emphasized that novel clinical candidates should be evaluated in animal models for treatment-resistant SZ. In conclusion, the plurality of available in vitro and in vivo models is a consequence of the complex nature of SZ, and there are extensive possibilities for their integration. Future development of more efficient antipsychotics reflecting the pleiotropy of symptoms in SZ requires the incorporation of various models into one uniting model of the multifactorial disorder and use of this model for the evaluation of new drugs.

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

Cited by 24 publications

References 42 publications

LY354740 Reduces Extracellular Glutamate Concentration, Inhibits Phosphorylation of Fyn/NMDARs, and Expression of PLK2/pS129 α-Synuclein in Mice Treated With Acute or Sub-Acute MPTP

LY354740 Reduces Extracellular Glutamate Concentration, Inhibits Phosphorylation of Fyn/NMDARs, and Expression of PLK2/pS129 α-Synuclein in Mice Treated With Acute or Sub-Acute MPTP

Serotonergic metamodulation of mGlu23 receptors, a new mechanism for pain management: the case of trazodone

In Vitro and In Vivo Models for the Investigation of Potential Drugs Against Schizophrenia

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