2. Academic Validation
  3. 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

  • J Pharmacol Exp Ther. 2015 Apr;353(1):213-33. doi: 10.1124/jpet.114.222463.
Lothar Lindemann 1,  Richard H Porter 2,  Sebastian H Scharf 2,  Basil Kuennecke 2,  Andreas Bruns 2,  Markus von Kienlin 2,  Anthony C Harrison 2,  Axel Paehler 2,  Christoph Funk 2,  Andreas Gloge 2,  Manfred Schneider 2,  Neil J Parrott 2,  Liudmila Polonchuk 2,  Urs Niederhauser 2,  Stephen R Morairty 2,  Thomas S Kilduff 2,  Eric Vieira 2,  Sabine Kolczewski 2,  Juergen Wichmann 2,  Thomas Hartung 2,  Michael Honer 2,  Edilio Borroni 2,  Jean-Luc Moreau 2,  Eric Prinssen 2,  Will Spooren 2,  Joseph G Wettstein 2,  Georg Jaeschke 2
Affiliations

Affiliations

  • 1 Roche Pharmaceutical Research and Early Development, Discovery Neuroscience, Neuroscience, Ophthalmology, and Rare Diseases (L.L., S.H.S., B.K., A.B., M.v.K., M.H., E.B., E.P., W.S., J.G.W.), Discovery Chemistry (E.V., S.K., J.W., G.J.), Operations for Neuroscience, Ophthalmology, and Rare Diseases (R.H.P., J.-L.M.), Pharmaceutical Sciences (A.C.H., A.P., C.F., A.G., M.S., N.J.P., L.P., U.N.), and Small Molecules Process Research and Synthesis (T.H.), Roche Innovation Center Basel, Basel, Switzerland; and Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, California (S.R.M., T.S.K.) lothar.lindemann@roche.com.
  • 2 Roche Pharmaceutical Research and Early Development, Discovery Neuroscience, Neuroscience, Ophthalmology, and Rare Diseases (L.L., S.H.S., B.K., A.B., M.v.K., M.H., E.B., E.P., W.S., J.G.W.), Discovery Chemistry (E.V., S.K., J.W., G.J.), Operations for Neuroscience, Ophthalmology, and Rare Diseases (R.H.P., J.-L.M.), Pharmaceutical Sciences (A.C.H., A.P., C.F., A.G., M.S., N.J.P., L.P., U.N.), and Small Molecules Process Research and Synthesis (T.H.), Roche Innovation Center Basel, Basel, Switzerland; and Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, California (S.R.M., T.S.K.).
PMID: 25665805 DOI: 10.1124/jpet.114.222463
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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