mGlu2/3 receptor antagonism: A mechanism to induce rapid antidepressant effects without ketamine-associated side-effects

Pharmacol Biochem Behav. 2020 Mar:190:172854. doi: 10.1016/j.pbb.2020.172854. Epub 2020 Jan 16.


The consensus that ketamine can produce rapid-onset antidepressant effects in patients combined with the recent approval of S(+)-ketamine (esketamine, Spravato) as an antidepressant, has fueled the search for other compounds that might recapitulate the remarkable therapeutic benefits of ketamine. At the same time, discovery efforts have been additionally directed toward minimization of the tolerability, side-effect, and safety issues associated with ketamine. The history of thought on the viability of metabotropic 2/3 (mGlu2/3) receptor antagonism as a potential mechanism for inducing rapid-acting antidepressant effects is reviewed here. The biological basis for predicting antidepressant efficacy of mGlu2/3 receptor antagonists in depressed patients is also presented. This prediction is based upon convergent biochemical, neurochemical, electrophysiological, and behavioral data that indicate a striking homology in the substrates that underlie the effects of mGlu2/3 receptor antagonists and the known antidepressant ketamine. The data reviewed to date also demonstrate that the preclinical side-effect/tolerability and toxicology profile of mGlu2/3 receptor antagonists are not concerning. Finally, preclinical data on a relatively new mGlu2/3 receptor antagonist, LY3020371, and its orally-bioavailable prodrug, LY3027788, are reviewed. The data on this mechanism provides optimism for successful translation of the mGlu2/3 receptor antagonist hypothesis into therapeutics for those suffering from depression.

Keywords: Ketamine; LY3020371; MGS0039; mGlu2/3 receptor antagonists.

Publication types

  • Review

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology*
  • Antidepressive Agents / therapeutic use
  • Cyclohexanes / pharmacology*
  • Cyclohexanes / therapeutic use
  • Depression / drug therapy
  • Excitatory Amino Acid Antagonists / adverse effects
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Excitatory Amino Acid Antagonists / therapeutic use
  • Humans
  • Ketamine / adverse effects
  • Ketamine / pharmacology
  • Ketamine / therapeutic use
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors*


  • 2-amino-3-((3,4-difluorophenyl)sulfanylmethyl)-4-hydroxy-bicyclo(3.1.0)hexane-2,6-dicarboxylic acid hydrochloride
  • Antidepressive Agents
  • Cyclohexanes
  • Excitatory Amino Acid Antagonists
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor 2
  • Esketamine
  • Ketamine
  • metabotropic glutamate receptor 4