Negative allosteric modulation of metabotropic glutamate receptor 5 results in broad spectrum activity relevant to treatment resistant depression

Hughes, Zoë A.; Neal, Sarah J.; Smith, Deborah L.; Rizzo, Stacey J. Sukoff; Pulicicchio, Claudine; Lotarski, Susan M.; Lu, Shiao‐Ping; Dwyer, Jason M.; Brennan, Julie; Olsen, Michael A.; Bender, Corey N.; Kouranova, Evguenia; Andree, Terrance H.; Harrison, Jim; Whiteside, Garth T.; Springer, Dane M.; O’Neil, Steven V.; Leonard, Sarah K.; Schechter, Lee E.; Dunlop, John; Rosenzweig‐Lipson, Sharon; Ring, Robert H.

doi:10.1016/j.neuropharm.2012.04.007

Cited by 73 publications

(45 citation statements)

References 53 publications

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“…EEG recordings revealed that repeated once-daily administration of basimglurant decreased the REM/non-REM ratio during the active period, and increased wakefulness and subsequent non-REM delta power. These observations are in agreement with EEG data reported for single-dose studies in rats with mavoglurant and GRN-529 [4-difluoromethoxy-3-(pyridine-2-ylethynyl)phenyl)5H-pyrrolo [3,4-b]pyridine-6(7H)-yl methanone] (Hughes et al, 2013). Disturbances of the sleep-wake pattern and EEG activity are a hallmark of MDD, contributing to daytime sleepiness as well as apathy and lethargy (Ahmadi et al, 2010).…”

Section: Discussionsupporting

confidence: 88%

“…These results are particularly relevant as the CMS method is considered a disease model for depression with good face-validity (Moreau, 2002;Nestler and Hyman, 2010), reflecting several key aspects of the human condition including a reduced hedonic drive, altered sleep/wake pattern, and endocrine changes in the hypothalamic-pituitary-adrenal axis (Moreau et al, 1995;Grippo et al, 2005). The dose-dependent reduction of immobility time by basimglurant in the FST, a screening procedure used for the profiling of antidepressants (Nestler and Hyman, 2010), is in agreement of what has been reported for other mGlu5 NAMs (Liu et al, 2012;Hughes et al, 2013). Moreover, fMRI recordings Basimglurant, an mGlu5 NAM in Development for Depression Fig.…”

Section: Discussionsupporting

confidence: 73%

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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: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 73%

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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“…dose-dependent attenuation of cocaine self-administration in a dose range that also showed anxiolytic-and antidepressantlike activity comparable with full mGlu 5 NAMs (Kenny et al, 2005;Paterson and Markou, 2005;Amato et al, 2013;Hughes et al, 2013;Keck et al, 2014). Dose-dependent effects of partial and full mGlu 5 NAMs in these assays corresponded with increasing in vivo mGlu 5 occupancy, demonstrating an orderly occupancy-to-efficacy relationship (see Table 1).…”

Section: Discussionmentioning

confidence: 80%

“…Another possible explanation is that the psychotomimetic effects of full mGlu 5 NAMs are associated with inverse agonist activity (Gasparini et al, 1999;Porter et al, 2005). Although multiple reports demonstrate potential for novel mGlu 5 NAMs to reduce cocaine self-administration as well as antidepressant-and anxiolyticlike activity (Keck et al, 2012(Keck et al, , 2014Amato et al, 2013;Felts et al, 2013;Hughes et al, 2013;Rook et al, 2015), a remaining challenge includes developing compounds with a substantial therapeutic window.…”

Section: Introductionmentioning

confidence: 99%

Partial mGlu5 Negative Allosteric Modulators Attenuate Cocaine-Mediated Behaviors and Lack Psychotomimetic-Like Effects

Gould

Amato

Bubser

et al. 2015

Neuropsychopharmacol

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Cocaine abuse remains a public health concern for which pharmacotherapies are largely ineffective. Comorbidities between cocaine abuse, depression, and anxiety support the development of novel treatments targeting multiple symptom clusters. Selective negative allosteric modulators (NAMs) targeting the metabotropic glutamate receptor 5 (mGlu 5 ) subtype are currently in clinical trials for the treatment of multiple neuropsychiatric disorders and have shown promise in preclinical models of substance abuse. However, complete blockade or inverse agonist activity by some full mGlu 5 NAM chemotypes demonstrated adverse effects, including psychosis in humans and psychotomimetic-like effects in animals, suggesting a narrow therapeutic window. Development of partial mGlu 5 NAMs, characterized by their submaximal but saturable levels of blockade, may represent a novel approach to broaden the therapeutic window. To understand potential therapeutic vs adverse effects in preclinical behavioral assays, we examined the partial mGlu 5 NAMs, M-5MPEP and Br-5MPEPy, in comparison with the full mGlu 5 NAM MTEP across models of addiction and psychotomimetic-like activity. M-5MPEP, Br-5MPEPy, and MTEP dose-dependently decreased cocaine self-administration and attenuated the discriminative stimulus effects of cocaine. M-5MPEP and Br-5MPEPy also demonstrated antidepressant-and anxiolytic-like activity. Dose-dependent effects of partial and full mGlu 5 NAMs in these assays corresponded with increasing in vivo mGlu 5 occupancy, demonstrating an orderly occupancy-to-efficacy relationship. PCP-induced hyperlocomotion was potentiated by MTEP, but not by M-5MPEP and Br-5MPEPy. Further, MTEP, but not M-5MPEP, potentiated the discriminative-stimulus effects of PCP. The present data suggest that partial mGlu 5 NAM activity is sufficient to produce therapeutic effects similar to full mGlu 5 NAMs, but with a broader therapeutic index.

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“…Group II mGlu receptors are also attractive targets for addiction and depression Moussawi and Kalivas, 2010;Chaki et al, 2013). Inhibitors of mGlu 5 have demonstrated efficacy in preclinical studies for anxiety, depression, and Parkinson's disease Levodopa-induced dyskinesias (Porter et al, 2005;Li et al, 2006;Belozertseva et al, 2007;Rylander et al, 2010;Hughes et al, 2013). Promisingly, multiple mGlu 5 inhibitors have reached (Berry-Kravis et al, 2009;Keywood et al, 2009;Zerbib et al, 2010) or are currently in phase II clinical trials (www.clinicalTrials.gov) with varying successes and failures for fragile X syndrome, Parkinson's disease Levodopa-induced dyskinesias, gastroesophogeal reflux disorder, and migraine.…”

Section: Introductionmentioning

confidence: 99%

Molecular Insights into Metabotropic Glutamate Receptor Allosteric Modulation

Gregory

Conn

2015

Mol Pharmacol

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The metabotropic glutamate (mGlu) receptors are a group of eight family C G protein-coupled receptors that are expressed throughout the central nervous system (CNS) and periphery. Within the CNS the different subtypes are found in neurons, both pre-and/or postsynaptically, where they mediate modulatory roles and in glial cells. The mGlu receptor family provides attractive targets for numerous psychiatric and neurologic disorders, with the majority of discovery programs focused on targeting allosteric sites, with allosteric ligands now available for all mGlu receptor subtypes. However, the development of allosteric ligands remains challenging. Biased modulation, probe dependence, and molecular switches all contribute to the complex molecular pharmacology exhibited by mGlu receptor allosteric ligands. In recent years we have made significant progress in our understanding of this molecular complexity coupled with an increased understanding of the structural basis of mGlu allosteric modulation.

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Negative allosteric modulation of metabotropic glutamate receptor 5 results in broad spectrum activity relevant to treatment resistant depression

Cited by 73 publications

References 53 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

Partial mGlu5 Negative Allosteric Modulators Attenuate Cocaine-Mediated Behaviors and Lack Psychotomimetic-Like Effects

Molecular Insights into Metabotropic Glutamate Receptor Allosteric Modulation

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