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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; Funk, Christoph; Gloge, Andreas; Schneider, Manfred; Parrott, Neil J; Polonchuk, Liudmila; Niederhauser, Urs; Morairty, Stephen R; Kilduff, Thomas S; Vieira, Eric; Kolczewski, Sabine; Wichmann, Juergen; Hartung, Thomas; Honer, Michael; Borroni, Edilio; Moreau, Jean-Luc; Prinssen, Eric; Spooren, Will; Wettstein, Joseph G; Jaeschke, Georg.
Affiliation
  • Lindemann L; 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
  • Porter RH; 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
  • Scharf SH; 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
  • Kuennecke B; 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
  • Bruns A; 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
  • von Kienlin M; 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
  • Harrison AC; 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
  • Paehler A; 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
  • Funk C; 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
  • Gloge A; 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
  • Schneider M; 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
  • Parrott NJ; 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
  • Polonchuk L; 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
  • Niederhauser U; 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
  • Morairty SR; 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
  • Kilduff TS; 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
  • Vieira E; 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
  • Kolczewski S; 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
  • Wichmann J; 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
  • Hartung T; 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
  • Honer M; 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
  • Borroni E; 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
  • Moreau JL; 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
  • Prinssen E; 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
  • Spooren W; 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
  • Wettstein JG; 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
  • Jaeschke G; 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
J Pharmacol Exp Ther ; 353(1): 213-33, 2015 Apr.
Article in En | MEDLINE | ID: mdl-25665805
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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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pyridines / Anti-Anxiety Agents / Depression / Receptor, Metabotropic Glutamate 5 / Imidazoles / Antidepressive Agents Limits: Animals Language: En Journal: J Pharmacol Exp Ther Year: 2015 Document type: Article
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pyridines / Anti-Anxiety Agents / Depression / Receptor, Metabotropic Glutamate 5 / Imidazoles / Antidepressive Agents Limits: Animals Language: En Journal: J Pharmacol Exp Ther Year: 2015 Document type: Article