Cognitive impairment in major depression and the mGlu2 receptor as a therapeutic target

Goeldner, Celia; Ballard, Theresa M.; Knoflach, Frédéric; Wichmann, Juergen; Gatti, Silvia; Umbricht, Daniel

doi:10.1016/j.neuropharm.2012.08.001

Cited by 87 publications

(54 citation statements)

References 130 publications

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“…The literature and our own work suggest that mGlu2/3 inhibitors have procognitive properties in a range of preclinical models of short-term and long-term memory, executive function, and impulse control (Higgins et al, 2004;Spinelli et al, 2005;Marek, 2010;Goeldner et al, 2013), which makes them interesting candidates to address cognitive deficits in MDD (Goeldner et al, 2013). For mGlu5, the situation is different because studies conducted in wild-type animals suggest that mGlu5 NAMs in general have no procognitive properties (Petersen et al, 2002;Ballard et al, 2005;Ahnaou et S.E.M., with n = 8 rats per group.…”

Section: Discussionmentioning

confidence: 95%

“…Cognitive deficits in MDD in general have received little attention to date, which is in part due to the fact that commonly used rating scales such as the Montgomery-Åsberg Depression Rating Scale (MADRS) and Quick Inventory of Depressive Symptomatology (QIDS) do not capture cognitive function very well. The picture is further complicated by the discrepancy between selfreported and objectively measured cognitive deficits in depressed patients, and by an apparent disconnect between the severity of depressive symptoms and cognitive functioning (Goeldner et al, 2013). Here, the possible interplay, especially between attention and executive function on the one side and symptoms of apathy/lethargy and motivation in depression on the other, warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacology of Basimglurant (RO4917523, RG7090), a Unique Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator in Clinical Development for Depression

Lindemann

Porter

Scharf

et al. 2015

J Pharmacol Exp Ther

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Major depressive disorder (MDD) is a serious public health burden and a leading cause of disability. Its pharmacotherapy is currently limited to modulators of monoamine neurotransmitters and secondgeneration antipsychotics. Recently, glutamatergic approaches for the treatment of MDD have increasingly received attention, and preclinical research suggests that metabotropic glutamate receptor 5 (mGlu5) inhibitors have antidepressant-like properties. Basimglurant (2-chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine) is a novel mGlu5 negative allosteric modulator currently in phase 2 clinical development for MDD and fragile X syndrome. Here, the comprehensive preclinical pharmacological profile of basimglurant is presented with a focus on its therapeutic potential for MDD and drug-like properties. Basimglurant is a potent, selective, and safe mGlu5 inhibitor with good oral bioavailability and long half-life supportive of once-daily administration, good brain penetration, and high in vivo potency. It has antidepressant properties that are corroborated by its functional magnetic imaging profile as well as anxiolytic-like and antinociceptive features. In electroencephalography recordings, basimglurant shows wakepromoting effects followed by increased delta power during subsequent non-rapid eye movement sleep. In microdialysis studies, basimglurant had no effect on monoamine transmitter levels in the frontal cortex or nucleus accumbens except for a moderate increase of accumbal dopamine, which is in line with its lack of pharmacological activity on monoamine reuptake transporters. These data taken together, basimglurant has favorable drug-like properties, a differentiated molecular mechanism of action, and antidepressant-like features that suggest the possibility of also addressing important comorbidities of MDD including anxiety and pain as well as daytime sleepiness and apathy or lethargy.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Pharmacology of Basimglurant (RO4917523, RG7090), a Unique Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator in Clinical Development for Depression

Lindemann

Porter

Scharf

et al. 2015

J Pharmacol Exp Ther

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“…In one study, cognitive functions have been monitored in patients treated with escitalopram (SSRI) or duloxetine (SNRI); an improvement in working memory, processing speed, and visual episodic memory was best observed with duloxetine (Herrera-Guzman et al 2009. To further address the effects of antidepressants on cognitive improvement more studies are needed and understanding this relationship would help design new and more efficacious therapeutic interventions (Goeldner et al 2013). Along the same line, more research is needed to unravel the role of hippocampal network and neurogenesis in the onset and recovery of cognitive alterations in MDD.…”

Section: Antidepressants and Cognitive Impairmentmentioning

confidence: 99%

Role of Adult Hippocampal Neurogenesis in Cognition in Physiology and Disease: Pharmacological Targets and Biomarkers

Costa

Lugert

Jagasia

2015

Handbook of Experimental Pharmacology

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Adult hippocampal neurogenesis is a remarkable form of brain structural plasticity by which new functional neurons are generated from adult neural stem cells/precursors. Although the precise role of this process remains elusive, adult hippocampal neurogenesis is important for learning and memory and it is affected in disease conditions associated with cognitive impairment, depression, and anxiety. Immature neurons in the adult brain exhibit an enhanced structural and synaptic plasticity during their maturation representing a unique population of neurons to mediate specific hippocampal function. Compelling preclinical evidence suggests that hippocampal neurogenesis is modulated by a broad range of physiological stimuli which are relevant in cognitive and emotional states. Moreover, multiple pharmacological interventions targeting cognition modulate adult hippocampal neurogenesis. In addition, recent genetic approaches have shown that promoting neurogenesis can positively modulate cognition associated with both physiology and disease. Thus the discovery of signaling pathways that enhance adult neurogenesis may lead to therapeutic strategies for improving memory loss due to aging or disease. This chapter endeavors to review the literature in the field, with particular focus on (1) the role of hippocampal neurogenesis in cognition in physiology and disease; (2) extrinsic and intrinsic signals that modulate hippocampal neurogenesis with a focus on pharmacological targets; and (3) efforts toward novel strategies pharmacologically targeting neurogenesis and identification of biomarkers of human neurogenesis.

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“…Two PAMs entered clinical trials, AZD8529 of AstraZeneca and JNJ-40411813 (also known as ADX71149) from Janssen/Addex [24][25][26][27][28][29]. A number of mGlu 2 negative allosteric modulators (NAMs) have been characterized in vivo, including a recent series of NAMs from Janssen and RO4491533 and decoglurant from Roche, of which the latter also advanced into clinical trials [30][31][32][33]. Taken together, discovery efforts have resulted in a great diversity of selective and high affinity mGlu 2 ligands, but no compounds have successfully passed clinical evaluation.…”

Section: Introductionmentioning

confidence: 99%

Constitutive activity of the metabotropic glutamate receptor 2 explored with a whole-cell label-free biosensor

Doornbos

Linden

Vereyken

et al. 2018

Biochemical Pharmacology

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Label-free cellular assays using a biosensor provide new opportunities for studying G protein-coupled receptor (GPCR) signaling. As opposed to conventional in vitro assays, integrated receptor-mediated cellular responses are determined in real-time rather than a single downstream signaling pathway. In this study, we examined the potential of a label-free whole cell impedance-based biosensor system (i.e. xCELLigence) to study the pharmacology of one GPCR in particular, the mGlu 2 receptor. This receptor is a target for the treatment of several psychiatric diseases such as schizophrenia and depression.After optimization of assay conditions to prevent interference of endogenous glutamate in the culture medium, detailed pharmacological assessments were performed. Concentration-response curves showed a concentration-dependent increase in impedance for agonists and positive allosteric modulators, whereas receptor inhibition by an antagonist or negative allosteric modulator resulted in a concentration-dependent decrease in cellular impedance. Interestingly, constitutive receptor activity was observed that was decreased by LY341495, which therefore behaved as an inverse agonist here, a property that was heretofore unappreciated. This was confirmed by concentration-dependent modulation of LY341495 potency and efficacy by a allosteric modulators.In summary, the use of the xCELLigence system to study mGlu 2 receptor pharmacology was validated. This is the first class C GPCR to be characterized extensively by such method, opening new avenues to study receptor pharmacology including inverse agonism and demonstrating its value for future drug discovery efforts of mGlu receptors as well as other GPCRs.

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Cognitive impairment in major depression and the mGlu2 receptor as a therapeutic target

Cited by 87 publications

References 130 publications

Pharmacology of Basimglurant (RO4917523, RG7090), a Unique Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator in Clinical Development for Depression

Pharmacology of Basimglurant (RO4917523, RG7090), a Unique Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator in Clinical Development for Depression

Role of Adult Hippocampal Neurogenesis in Cognition in Physiology and Disease: Pharmacological Targets and Biomarkers

Constitutive activity of the metabotropic glutamate receptor 2 explored with a whole-cell label-free biosensor

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