Skip to main content
Journal cover image

The metabotropic glutamate receptor subtype 5 antagonist fenobam is analgesic and has improved in vivo selectivity compared with the prototypical antagonist 2-methyl-6-(phenylethynyl)-pyridine.

Publication ,  Journal Article
Montana, MC; Cavallone, LF; Stubbert, KK; Stefanescu, AD; Kharasch, ED; Gereau, RW
Published in: J Pharmacol Exp Ther
September 2009

Metabotropic glutamate receptor subtype 5 (mGlu5) has been demonstrated to play a role in the modulation of numerous nociceptive modalities. When administered via peripheral, intrathecal, or systemic routes, mGlu5 antagonists have analgesic properties in a variety of preclinical pain models. Despite a wealth of data supporting the use of mGlu5 antagonists to treat pain, studies have been limited to preclinical animal models due to a lack of mGlu5 antagonists that are approved for use in humans. It has been demonstrated previously that fenobam [N-(3-chlorophenyl)-N'-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea], an anxiolytic shown to be safe and effective in human trials, is a selective and potent noncompetitive antagonist of mGlu5 (J Pharmacol Exp Ther 315:711-721, 2005). Here, we report a series of studies aimed at testing whether fenobam, similar to the prototypical mGlu5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP), has analgesic properties in mice. We show that fenobam reduces formalin-induced pain behaviors and relieves established inflammation-induced thermal hypersensitivity in mice. Similar results were seen with MPEP. Administration of fenobam resulted in an increase in locomotor activity in the open-field task but did not impair performance on the accelerating Rotarod. Analysis of brain and plasma fenobam levels indicated that fenobam is rapidly concentrated in brain after intraperitoneal administration in mice but is essentially cleared from circulation within 1 h after injection. Fenobam had no analgesic effect in mGlu5 knockout mice, whereas the prototypical antagonist MPEP retained significant analgesic efficacy in mGlu5 knockouts. These results demonstrate that fenobam is analgesic in mice and has an improved in vivo selectivity for mGlu5 over MPEP.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

J Pharmacol Exp Ther

DOI

EISSN

1521-0103

Publication Date

September 2009

Volume

330

Issue

3

Start / End Page

834 / 843

Location

United States

Related Subject Headings

  • Receptors, Kainic Acid
  • Quality Control
  • Pyridines
  • Postural Balance
  • Pharmacology & Pharmacy
  • Pain Measurement
  • Pain
  • Motor Activity
  • Mice, Inbred C57BL
  • Mice
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Montana, M. C., Cavallone, L. F., Stubbert, K. K., Stefanescu, A. D., Kharasch, E. D., & Gereau, R. W. (2009). The metabotropic glutamate receptor subtype 5 antagonist fenobam is analgesic and has improved in vivo selectivity compared with the prototypical antagonist 2-methyl-6-(phenylethynyl)-pyridine. J Pharmacol Exp Ther, 330(3), 834–843. https://doi.org/10.1124/jpet.109.154138
Montana, Michael C., Laura F. Cavallone, Kristi K. Stubbert, Andrei D. Stefanescu, Evan D. Kharasch, and Robert W. Gereau. “The metabotropic glutamate receptor subtype 5 antagonist fenobam is analgesic and has improved in vivo selectivity compared with the prototypical antagonist 2-methyl-6-(phenylethynyl)-pyridine.J Pharmacol Exp Ther 330, no. 3 (September 2009): 834–43. https://doi.org/10.1124/jpet.109.154138.
Montana, Michael C., et al. “The metabotropic glutamate receptor subtype 5 antagonist fenobam is analgesic and has improved in vivo selectivity compared with the prototypical antagonist 2-methyl-6-(phenylethynyl)-pyridine.J Pharmacol Exp Ther, vol. 330, no. 3, Sept. 2009, pp. 834–43. Pubmed, doi:10.1124/jpet.109.154138.
Journal cover image

Published In

J Pharmacol Exp Ther

DOI

EISSN

1521-0103

Publication Date

September 2009

Volume

330

Issue

3

Start / End Page

834 / 843

Location

United States

Related Subject Headings

  • Receptors, Kainic Acid
  • Quality Control
  • Pyridines
  • Postural Balance
  • Pharmacology & Pharmacy
  • Pain Measurement
  • Pain
  • Motor Activity
  • Mice, Inbred C57BL
  • Mice