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

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.

• Authors: Atsuyuki Kohara, Yukinori Nagakura, Tetsuo Kiso, Takashi Toya, Tomonari Watabiki, Seiji Tamura, Yoshitsugu Shitaka, Hirotsune Itahana, Masamichi Okada
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 571 Issue 1 Pg. 8-16 (Sep 24 2007) ISSN: 0014-2999 [Print] Netherlands
• PMID: 17597604 (Publication Type: Journal Article)

Chemical References

• (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

Topics

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