Antinociceptive profile of a selective metabotropic glutamate receptor 1 antagonist YM-230888 in chronic pain rodent models

Eur J Pharmacol. 2007 Sep 24;571(1):8-16. doi: 10.1016/j.ejphar.2007.05.030. Epub 2007 Jun 5.

Abstract

Metabotropic glutamate receptor 1 (mGlu(1) receptor) has been suggested to play an important role in pain transmission. In this study, the effects of a newly-synthesized mGlu(1) receptor antagonist, (R)-N-cycloheptyl-6-({[(tetrahydro-2-furyl)methyl]amino}methyl)thieno[2,3-d]pyrimidin-4-ylamine (YM-230888), were examined in a variety of rodent chronic pain models in order to characterize the potential analgesic profile of mGlu(1) receptor blockade. YM-230888 bound an allosteric site of mGlu(1) receptor with a K(i) value of 13+/-2.5 nM and inhibited mGlu(1)-mediated inositol phosphate production in rat cerebellar granule cells with an IC(50) value of 13+/-2.4 nM. It showed selectivity for mGlu(1) versus mGlu(2)-mGlu(7) subtypes and ionotropic glutamate receptors. YM-230888 recovered mechanical allodynia with an ED(50) value of 8.4 mg/kg p.o. in L5/L6 spinal nerve ligation models. It also showed antinociceptive response at doses of 10 and 30 mg/kg p.o. in streptozotocin-induced hyperalgesia models. In addition, it significantly reduced pain parameters at a dose of 30 mg/kg p.o. in complete Freund's adjuvant-induced arthritic pain models. Although YM-230888 showed no significant effect on rotarod performance time at doses of 10 or 30 mg/kg p.o., it significantly decreased it at a dose of 100 mg/kg p.o. On the other hand, YM-230888 showed no significant sedative effect in locomotor activity measurement up to 100 mg/kg p.o. These results suggest that the blockade of mGlu(1) receptors is an attractive target for analgesics. YM-230888 has potential as a new analgesic agent for the treatment of various chronic pain conditions. In addition, YM-230888 may be a useful tool for the investigation of mGlu(1) receptors.

MeSH terms

  • Analgesics / metabolism
  • Analgesics / pharmacokinetics
  • Analgesics / pharmacology*
  • Animals
  • Arthritis, Experimental / physiopathology
  • Arthritis, Experimental / prevention & control
  • Benzimidazoles / metabolism
  • Binding, Competitive
  • Cell Line
  • Cells, Cultured
  • Chronic Disease
  • Cycloheptanes / metabolism
  • Cycloheptanes / pharmacokinetics
  • Cycloheptanes / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Kinetics
  • Ligation / adverse effects
  • Molecular Structure
  • Motor Activity / drug effects
  • Pain / etiology
  • Pain / physiopathology
  • Pain / prevention & control*
  • Pain Measurement / drug effects
  • Pain Measurement / methods
  • Pyrimidines / metabolism
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / pharmacology*
  • Radioligand Assay
  • Rats
  • Rats, Inbred Lew
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors*
  • Receptors, Metabotropic Glutamate / metabolism
  • Spinal Nerves / surgery
  • Thiazoles / metabolism
  • Tritium

Substances

  • (R)-N-cycloheptyl-6-((((tetrahydro-2-furyl)methyl)amino)methyl)thieno(2,3-d)pyrimidin-4-ylamine
  • 6-amino-N-cyclohexyl-N,3-dimethylthiazolo(3,2-a)benzimidazole-2-carboxamide
  • Analgesics
  • Benzimidazoles
  • Cycloheptanes
  • Pyrimidines
  • Receptors, Metabotropic Glutamate
  • Thiazoles
  • metabotropic glutamate receptor type 1
  • Tritium