JPET

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
 QUICK SEARCH:   [advanced]


     


Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on July 22, 2005; DOI: 10.1124/jpet.105.089839


0022-3565/05/3152-711-721$20.00
JPET 315:711-721, 2005
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
jpet.105.089839v1
315/2/711    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Porter, R. H. P.
Right arrow Articles by Malherbe, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Porter, R. H. P.
Right arrow Articles by Malherbe, P.

NEUROPHARMACOLOGY

Fenobam: A Clinically Validated Nonbenzodiazepine Anxiolytic Is a Potent, Selective, and Noncompetitive mGlu5 Receptor Antagonist with Inverse Agonist Activity

Richard H. P. Porter, Georg Jaeschke, Will Spooren, Theresa M. Ballard, Bernd Büttelmann, Sabine Kolczewski, Jens-Uwe Peters, Eric Prinssen, Jürgen Wichmann, Eric Vieira, Andreas Mühlemann, Silvia Gatti, Vincent Mutel1, and Pari Malherbe

Pharma Division, Discovery Research CNS (R.H.P.P., W.S., T.M.B., A.M., E.P., A.M., S.G., V.M., P.M.) and Chemistry (G.J., B.B., S.K., J.-U.P., J.W., E.V.), F. Hoffmann-La Roche, Basel, Switzerland

Fenobam [N-(3-chlorophenyl)-N'-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea] is an atypical anxiolytic agent with unknown molecular target that has previously been demonstrated both in rodents and human to exert anxiolytic activity. Here, we report that fenobam is a selective and potent metabotropic glutamate (mGlu)5 receptor antagonist acting at an allosteric modulatory site shared with 2-methyl-6-phenylethynyl-pyridine (MPEP), the protypical selective mGlu5 receptor antagonist. Fenobam inhibited quisqualate-evoked intracellular calcium response mediated by human mGlu5 receptor with IC50 = 58 ± 2 nM. It acted in a noncompetitive manner, similar to MPEP and demonstrated inverse agonist properties, blocking 66% of the mGlu5 receptor basal activity (in an over expressed cell line) with an IC50 = 84 ± 13 nM. [3H]Fenobam bound to rat and human recombinant receptors with Kd values of 54 ± 6 and 31 ± 4 nM, respectively. MPEP inhibited [3H]fenobam binding to human mGlu5 receptors with a Ki value of 6.7 ± 0.7 nM, indicating a common binding site shared by both allosteric antagonists. Fenobam exhibits anxiolytic activity in the stress-induced hyperthermia model, Vogel conflict test, Geller-Seifter conflict test, and conditioned emotional response with a minimum effective dose of 10 to 30 mg/kg p.o. Furthermore, fenobam is devoid of GABAergic activity, confirming previous reports that fenobam acts by a mechanism distinct from benzodiazepines. The non-GABAergic activity of fenobam, coupled with its robust anxiolytic activity and reported efficacy in human in a double blind placebo-controlled trial, supports the potential of developing mGlu5 receptor antagonists with an improved therapeutic window over benzodiazepines as novel anxiolytic agents.


Received for publication May 19, 2005
Accepted July 19, 2005.

Address correspondence to: Dr. Richard Porter, F. Hoffmann-La Roche, PRBD-N, Bldg. 69/452, CH-4070 Basel, Switzerland. E-mail: richard.porter{at}roche.com




This article has been cited by other articles:


Home page
J. Pharmacol. Exp. Ther.Home page
L. Wang, B. Martin, R. Brenneman, L. M. Luttrell, and S. Maudsley
Allosteric Modulators of G Protein-Coupled Receptors: Future Therapeutics for Complex Physiological Disorders
J. Pharmacol. Exp. Ther., November 1, 2009; 331(2): 340 - 348.
[Abstract] [Full Text] [PDF]


Home page
NeuroscientistHome page
R. Machado-Vieira, H. K. Manji, and C. A. Zarate
The Role of the Tripartite Glutamatergic Synapse in the Pathophysiology and Therapeutics of Mood Disorders
Neuroscientist, October 1, 2009; 15(5): 525 - 539.
[Abstract] [PDF]


Home page
J. Pharmacol. Exp. Ther.Home page
M. C. Montana, L. F. Cavallone, K. K. Stubbert, A. D. Stefanescu, E. D. Kharasch, and R. W. Gereau IV
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., September 1, 2009; 330(3): 834 - 843.
[Abstract] [Full Text] [PDF]


Home page
J. Med. Genet.Home page
C D'Hulst and R F Kooy
Fragile X syndrome: from molecular genetics to therapy
J. Med. Genet., September 1, 2009; 46(9): 577 - 584.
[Abstract] [Full Text] [PDF]


Home page
J. Med. Genet.Home page
E Berry-Kravis, D Hessl, S Coffey, C Hervey, A Schneider, J Yuhas, J Hutchison, M Snape, M Tranfaglia, D V Nguyen, et al.
A pilot open label, single dose trial of fenobam in adults with fragile X syndrome
J. Med. Genet., April 1, 2009; 46(4): 266 - 271.
[Abstract] [Full Text] [PDF]


Home page
PediatricsHome page
R. J. Hagerman, E. Berry-Kravis, W. E. Kaufmann, M. Y. Ono, N. Tartaglia, A. Lachiewicz, R. Kronk, C. Delahunty, D. Hessl, J. Visootsak, et al.
Advances in the Treatment of Fragile X Syndrome
Pediatrics, January 1, 2009; 123(1): 378 - 390.
[Abstract] [Full Text] [PDF]




Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
 Molecular Interventions Drug Metabolism and Disposition

Copyright © 2005 by the American Society for Pharmacology and Experimental Therapeutics.