PT  - JOURNAL ARTICLE
AU  - Porter, Richard H. P.
AU  - Jaeschke, Georg
AU  - Spooren, Will
AU  - Ballard, Theresa M.
AU  - Büttelmann, Bernd
AU  - Kolczewski, Sabine
AU  - Peters, Jens-Uwe
AU  - Prinssen, Eric
AU  - Wichmann, Jürgen
AU  - Vieira, Eric
AU  - Mühlemann, Andreas
AU  - Gatti, Silvia
AU  - Mutel, Vincent
AU  - Malherbe, Pari
TI  - Fenobam: A Clinically Validated Nonbenzodiazepine Anxiolytic Is a Potent, Selective, and Noncompetitive mGlu5 Receptor Antagonist with Inverse Agonist Activity
AID  - 10.1124/jpet.105.089839
DP  - 2005 Nov 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 711--721
VI  - 315
IP  - 2
4099  - http://jpet.aspetjournals.org/content/315/2/711.short
4100  - http://jpet.aspetjournals.org/content/315/2/711.full
SO  - J Pharmacol Exp Ther2005 Nov 01; 315
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics