Cited by 107Treatment of Major DepressionNeuroscience and Neuropharmacology ResearchNeurotransmitter Receptor Influence on Behavior

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

Lindemann, Lothar, Porter, Richard H., Scharf, Sebastian H., Kuennecke, Basil, Bruns, Andreas, von Kienlin, Markus, Harrison, Anthony C., Paehler, Axel +19 more·2015·The Journal of Pharmacology and Experimental Therapeutics

Abstract

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 second-generation 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 wake-promoting 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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Crossref · 10.1124/jpet.114.222463

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  • Between 2008 and 2014, large clinical trials tested two mGluR5 antagonists, basimglurant and mavoglurant, and the GABAB agonist arbaclofen.

    “Large clinical trials were conducted between 2008 and 2014 (FIG. 2) for two mGluR5 antagonists (basimglurant66 and mavoglurant67) as well as a GABAB agonist (arbaclofen68) (BOX 2).”
  • Preclinical data and receptor occupancy measures in mice and healthy subjects showed that the study drugs entered the brain, bound their target receptors, and produced pharmacodynamic effects.

    “A wealth of preclinical data and direct receptor occupancy measures for basimglurant in mice66 and healthy subjects70 demonstrated that the study drugs entered the brain, engaged their target receptors and showed pharmacodynamic effects.”

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Authors
Lindemann, L., Porter, R. H., Scharf, S. H., Kuennecke, B., Bruns, A., von Kienlin, M., Harrison, A. C., Paehler, A., Funk, C., Gloge, A., Schneider, M., Parrott, N. J., Polonchuk, L., Niederhauser, U., Morairty, S. R., Kilduff, T. S., Vieira, E., Kolczewski, S., Wichmann, J., Hartung, T., Honer, M., Borroni, E., Moreau, J.-L., Prinssen, E., Spooren, W., Wettstein, J. G., & Jaeschke, G.
Affiliations
F. Hoffmann-La Roche AG (CH)
Venue
The Journal of Pharmacology and Experimental Therapeutics
Publisher
Elsevier BV
Published
2015-04
Volume
353
Issue
1
Pages
213-233
ISSN
0022-3565 (ISSN-L)
OpenAlex
W2155251656
Cited by
107
References
114
Citations by year
2026: 6 · 2025: 3 · 2024: 5 · 2023: 7 · 2022: 4 · 2021: 12 · 2020: 4 · 2019: 13 · 2018: 13 · 2017: 15 · 2016: 18 · 2015: 6
FWCI
12.97
Type
journal article
Language
en
Open access
closed
Locations
  • Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
metabotropic glutamate receptor 5, major depressive disorder, antidepressant mechanism, fragile X syndrome, monoamines, brain penetration, anxiolytic-like effects, antinociception, drug-likeness, pharmacokinetics
MeSH terms
Allosteric Regulation, Animals, Antidepressive Agents, Brain, Cells, Cultured, Cricetulus, Depression, Electroencephalography, Female, Imidazoles, Macaca fascicularis, Male, Pain, Pyridines, Radioligand Assay, Anti-Anxiety Agents, Biogenic Monoamines, Rats, Sprague-Dawley, Rats, Wistar, Mice, Urinary Bladder, Overactive, Drug Inverse Agonism, Receptor, Metabotropic Glutamate 5

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