title: Basimglurant for treatment of major depressive disorder: a novel negative allosteric modulator of metabotropic glutamate receptor 5.
abstract: BACKGROUND
  Metabotropic glutamate receptor 5 (mGlu5) negative allosteric modulators (NAM) such as 2-Methyl-6-(phenylethynyl)pyridine (MPEP) and 3-((2-Methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP) can produce antidepressant-like effects; an example being the forced swim test in rodents. It is therefore of high interest that a new mGlu5 NAM called basimglurant (RO4917523, RG7090) was recently introduced for clinical development in depression.
  
  
  METHODS
  The current article reports on the preclinical and clinical work with basimglurant which strongly supports its use for treatment of depression. The authors cover the pharmacodynamics, pharmacokinetics and safety and tolerability features of basimglurant together with its clinical efficacy in a clinical type II trial.
  
  
  CONCLUSIONS
  The antidepressant activity of basimglurant may be related to a preferential reduction of mGlu5 receptor signaling in distinct populations of cortical limbic GABA interneurons causing disinhibition of discrete glutamate neuronal networks in brain circuits of mood and emotion. Basimglurant's removal of mGlu5 receptor induced inhibition of D2 receptor signaling in A2A-D2-mGlu5 heteroreceptor complexes of ventral striato-pallidal GABA neurons mediating anti-reward may also play a role. Basimglurant is a highly promising antidepressant drug now in clinical development for depression. However, further clinical trials are highly warranted.
authors.affiliation: Karolinska Instituet, Department of Neuroscience , Retzius väg 8, 17177 Stockholm , Sweden +46 8 5248 7077 ; +46 8 315 721 ; kjell.fuxe@ki.se.
authors.forename: Kjell
authors.initials: K
authors.lastname: Fuxe
authors.forename: Dasiel O
authors.initials: DO
authors.lastname: Borroto-Escuela
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D000928:Antidepressive Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors
chemical_list: C000596770:2-chloro-4-(1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl)pyridine; D000928:Antidepressive Agents; D007093:Imidazoles; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5
keywords: antidepressant drug; basimglurant; depression; heteroreceptor complexes; major depressive disorder; metabotropic glutamate receptor 5; negative allosteric modulators