Pharmacological effects of the metabotropic glutamate receptor 1 antagonist compared with those of the metabotropic glutamate receptor 5 antagonist and metabotropic glutamate receptor 2/3 agonist in rodents: detailed investigations with a selective allosteric metabotropic glutamate receptor 1 antagonist, FTIDC [4-[1-(2-fluoropyridine-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide]

J Pharmacol Exp Ther. 2008 Aug;326(2):577-86. doi: 10.1124/jpet.108.138107. Epub 2008 May 16.

Abstract

The functional roles of metabotropic glutamate receptor (mGluR) 1 in integrative brain functions were investigated using a potent and selective mGluR1 allosteric antagonist, FTIDC [4-[1-(2-fluoropyridine-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide], in comparison with the mGluR5 allosteric antagonist and the mGluR2/3 orthosteric agonist in rodents. FTIDC reduced maternal separation-induced ultrasonic vocalization and stress-induced hyperthermia without affecting behaviors in the elevated plus maze. An mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), and an mGluR2/3 agonist, LY379268 [(1R,4R,5S,6R)-4-amino-2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid], showed anxiolytic activities in these models, suggesting involvement of postsynaptic mGluR1 in stress-related responses comparable with mGluR5 and mGluR2/3. Analgesic effects of FTIDC were seen in the formalin test but not in the tail immersion test. FTIDC selectively blocked methamphetamine-induced hyperlocomotion and disruption of prepulse inhibition, whereas MPEP and LY379268 did not alter those behaviors, suggesting that pharmacological blockade of mGluR1 could result in antipsychotic-like effects. FTIDC did not elicit catalepsy or impair motor functions at 10 times higher dose than doses showing antipsychotic-like action. In conclusion, blockade of mGluR1 showed antipsychotic-like effects without impairing motor functions, whereas blockade of mGluR5 and activation of mGluR2/3 did not display such activities.

Publication types

  • Comparative Study

MeSH terms

  • Allosteric Regulation
  • Animals
  • Anti-Anxiety Agents / chemistry
  • Anti-Anxiety Agents / pharmacology*
  • Behavior, Animal / drug effects*
  • Brain / drug effects
  • Brain / metabolism
  • Fever / drug therapy
  • Male
  • Maze Learning
  • Mice
  • Mice, Inbred C57BL
  • Motor Activity / drug effects
  • Pain / drug therapy
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate / agonists*
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors*
  • Reflex, Startle / drug effects
  • Triazoles / chemistry
  • Triazoles / pharmacology*
  • Vocalization, Animal / drug effects

Substances

  • 4-(1-(2-fluoropyridin-3-yl)-5-methyl-1H-1,2,3,-triazol-4-yl)-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide
  • Anti-Anxiety Agents
  • Grm5 protein, mouse
  • Grm5 protein, rat
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate
  • Triazoles
  • metabotropic glutamate receptor 2
  • metabotropic glutamate receptor 3
  • metabotropic glutamate receptor type 1