PT - JOURNAL ARTICLE AU - Lothar Lindemann AU - Richard H. Porter AU - Sebastian H. Scharf AU - Basil Kuennecke AU - Andreas Bruns AU - Markus von Kienlin AU - Anthony C. Harrison AU - Axel Paehler AU - Christoph Funk AU - Andreas Gloge AU - Manfred Schneider AU - Neil J. Parrott AU - Liudmila Polonchuk AU - Urs Niederhauser AU - Stephen R. Morairty AU - Thomas S. Kilduff AU - Eric Vieira AU - Sabine Kolczewski AU - Juergen Wichmann AU - Thomas Hartung AU - Michael Honer AU - Edilio Borroni AU - Jean-Luc Moreau AU - Eric Prinssen AU - Will Spooren AU - Joseph G. Wettstein AU - Georg Jaeschke TI - Pharmacology of Basimglurant (RO4917523, RG7090), a Unique Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator in Clinical Development for Depression AID - 10.1124/jpet.114.222463 DP - 2015 Apr 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 213--233 VI - 353 IP - 1 4099 - http://jpet.aspetjournals.org/content/353/1/213.short 4100 - http://jpet.aspetjournals.org/content/353/1/213.full SO - J Pharmacol Exp Ther2015 Apr 01; 353 AB - 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.