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

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 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.

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

“…These selective mGlu 5 NAMs have shown exciting efficacy across preclinical models (Emmitte, 2011;Christopoulos, 2014;Nickols and Conn, 2014) and in clinical development for the treatment of multiple CNS disorders (Berg et al, 2011;Jacquemont et al, 2011;Nickols and Conn, 2014;Lindemann et al, 2015).…”

Fragile X syndrome: Current insight

“…However it is still possible that the studies done till date were not long enough to show benefits, or that the drug may work in younger children. Currently another mGluR5 negative allosteric modulator, basimglurant is clinically found to be potent, selective, and safe with good oral bioavailability and long half-life, good brain penetration, and high in vivo potency [39]. It is now in Phase II trials for which results are still not released.…”

Pharmaco-EEG Studies in Animals: A History-Based Introduction to Contemporary Translational Applications

“…The central activity of ligands acting at 5HT7, mGluR2, mGluR5, mGluR7 and MCH1 has been characterised in rodents: inhibition of REM sleep occurrence was observed with 5HT7 antagonists [79,80,81], mGuR2 agonist and positive allosteric modulators (PAMs) [82,83], and with mGluR7 PAMs [84]. While mGluR2 antagonists and negative allosteric modulators (NAMs) and mGluR5 PAMs exhibit arousal-promoting properties [85,86,87], mGluR5 NAMs consolidated deep sleep time and cortical delta activity in preclinical as well as clinical studies [85,88,89]. Lastly, MCH1 antagonists decreased deep sleep without homeostatic recovery sleep [48].…”