Metabotropic glutamate receptor 4 novel agonist LSP1-2111 with anxiolytic, but not antidepressant-like activity, mediated by serotonergic and GABAergic systems

Wierońska, Joanna M.; Stachowicz, Katarzyna; Pałucha-Poniewiera, Agnieszka; Acher, Francine; Brański, Piotr; Pilc, Andrzej

doi:10.1016/j.neuropharm.2010.08.008

Cited by 55 publications

(38 citation statements)

References 57 publications

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“…However, ACPT-I administered i.p. failed to show efficacy in the FST and TST in mice (Stachowicz et al, 2009), whereas LSP1-2111 and Lu AF21934 were inactive in TST (Wiero nska et al, 2010;Sławi nska et al, 2013a). The lack of effect of Lu AF21934 in TST, however, needs to be taken with caution, as the compound had a motor-suppressant effect which could have confounded any increases in mobility in the TST (Sławi nska et al, 2013b).…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 ADX88178 in Rodent Models of Neuropsychiatric Disorders

Kalinichev

Poul

Boléa

et al. 2014

J Pharmacol Exp Ther

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There is growing evidence that activation of metabotropic glutamate receptor 4 (mGlu 4 ) leads to anxiolytic-and antipsychotic-like efficacy in rodent models, yet its relevance to depression-like reactivity remains unclear. Here, we present the pharmacological evaluation of ADX88178 [5-methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine], a novel potent, selective, and brain-penetrant positive allosteric modulator of the mGlu 4 receptor in rodent models of anxiety, obsessive compulsive disorder (OCD), fear, depression, and psychosis. ADX88178 dose-dependently reduced the number of buried marbles in the marble burying test and increased open-arm exploration in the elevated plus maze (EPM) test, indicative of anxiolyticlike efficacy. Target specificity of the effect in the EPM test was confirmed using male and female mGlu 4 receptor knockout mice. In mice, ADX88178 reduced the likelihood of conditioned freezing in the acquisition phase of the fear conditioning test, yet had no carryover effect in the expression phase. Also, ADX88178 dose-dependently reduced duration of immobility in the forced swim test, indicative of antidepressantlike efficacy. ADX88178 reduced DOI (2,5-dimethoxy-4-iodoamphetamine)-mediated head twitches (albeit with no dose-dependency), and MK-801 [(5S,10R)-(1)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine]-induced locomotor hyperactivity in mice, but was inactive in the conditioned avoidance response test in rats. The compound showed good specificity as it had no effect on locomotor activity in mice and rats at efficacious doses. Thus, allosteric activation of mGlu 4 receptors can be a promising new therapeutic approach for treatment of anxiety, OCD, fear-related disorders, and psychosis.

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Section: Discussionmentioning

confidence: 99%

Characterization of the Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 ADX88178 in Rodent Models of Neuropsychiatric Disorders

Kalinichev

Poul

Boléa

et al. 2014

J Pharmacol Exp Ther

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“…Stably transfected cells were grown to 60% confluence in supplemented DMEM. Several hours before the experiment (2,4,8,24, 48, or 72 h), mGlu receptor expression was induced by adding 0.75 µg/mL tetracycline. Twenty hours before the experiment, fetal bovine serum (FBS) and Glutamax I deprivation was performed.…”

Section: Forskolin-induced Camp Production Assaymentioning

confidence: 99%

“…Intervention in glutamatergic neurotransmission through the mGlu4 receptor has been proposed for the treatment of many neurodegenerative diseases, such as Parkinson disease, Alzheimer disease, stroke, and epilepsy. 3 The role of the mGlu4 receptor has proved itself to be also related with psychiatric disorders such as anxiety 4 and schizophrenia. 5,6 Thus, new mGlu4 receptor ligands, especially allosteric modulators with improved selectivity and reduced side effects, have become a very attractive target for therapeutic intervention.…”

Section: Introductionmentioning

confidence: 99%

Tetracycline-Based System for Controlled Inducible Expression of Group III Metabotropic Glutamate Receptors

et al. 2015

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A stable and inducible expression of metabotropic glutamate receptor type 4, 7, and 8 was obtained in T-REx 293 cells using the tetracycline system. Tetracycline administration to the cell medium resulted in rapid induction and timedependent expression of mGlu receptors, which also correlates with its functionality in a cAMP accumulation assay. The pharmacological properties of recombinant mGlu receptors were verified using orthosteric and allosteric ligands. Data suggest that the Tet-on inducible system is suitable for functional mGlu receptors' expression and characterization by means of the cAMP accumulation assay. It makes this system a precise, reproducible, and large-scale screening method, as well as a reasonable tool to study signaling properties of mGlu receptors.

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“…Thus, recent studies have found that both PAMs and orthosteric agonists of mGlu4 produce anxiolytic effects, which appear to be mediated via a modulation of GABAergic signalling [53, 251,252]. The role of mGlu7 is less clear, with pharmacological agents producing both anxiolytic [39, 253] and anxiogenic effects [238], and mGlu7 KO mice exhibiting reduced anxietyrelated behaviour [254], as well as a deficit in amygdaladependent fear learning [213].…”

Section: Anxietymentioning

confidence: 99%

Group III Metabotropic Glutamate Receptors: Pharmacology, Physiology and Therapeutic Potential

Mercier

Lodge

2014

Neurochem Res

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Glutamate, the primary excitatory neurotransmitter in the central nervous system (CNS), exerts neuromodulatory actions via the activation of metabotropic glutamate (mGlu) receptors. There are eight known mGlu receptor subtypes (mGlu1-8), which are widely expressed throughout the brain, and are divided into three groups (I-III), based on signalling pathways and pharmacological profiles. Group III mGlu receptors (mGlu4/6/7/8) are primarily, although not exclusively, localised on presynaptic terminals, where they act as both auto- and hetero-receptors, inhibiting the release of neurotransmitter. Until recently, our understanding of the role of individual group III mGlu receptor subtypes was hindered by a lack of subtype-selective pharmacological tools. Recent advances in the development of both orthosteric and allosteric group III-targeting compounds, however, have prompted detailed investigations into the possible functional role of these receptors within the CNS, and revealed their involvement in a number of pathological conditions, such as epilepsy, anxiety and Parkinson's disease. The heterogeneous expression of group III mGlu receptor subtypes throughout the brain, as well as their distinct distribution at glutamatergic and GABAergic synapses, makes them ideal targets for therapeutic intervention. This review summarises the advances in subtype-selective pharmacology, and discusses the individual roles of group III mGlu receptors in physiology, and their potential involvement in disease.

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Metabotropic glutamate receptor 4 novel agonist LSP1-2111 with anxiolytic, but not antidepressant-like activity, mediated by serotonergic and GABAergic systems

Cited by 55 publications

References 57 publications

Characterization of the Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 ADX88178 in Rodent Models of Neuropsychiatric Disorders

Characterization of the Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 ADX88178 in Rodent Models of Neuropsychiatric Disorders

Tetracycline-Based System for Controlled Inducible Expression of Group III Metabotropic Glutamate Receptors

Group III Metabotropic Glutamate Receptors: Pharmacology, Physiology and Therapeutic Potential

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