Received for publication May 20, 2005.
Revised July 19, 2005.
Accepted for publication July 19, 2005.

Fenobam: A clinically validated non-benzodiazepine anxiolytic is a potent, selective and non-competitive mGlu5 receptor antagonist with inverse agonist activity

Abstract

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 man to exert anxiolytic activity. Here we report that fenobam is a selective and potent mGlu5 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 [Ca²⁺]_i response mediated by human mGlu5 receptor with IC₅₀ = 58 ± 2 nM. It acted in a non-competitive 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 K_d values of 54 ± 6 nM and 31 ± 4 nM, respectively. MPEP inhibited [³H]fenobam binding to hmGlu5 receptors with a K_i 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 an MED of 10-30 mg/kg p.o. Furthermore, fenobam is devoid of GABA-ergic activity confirming previous reports that fenobam acts by a mechanism distinct from benzodiazepines. The non-GABA-ergic activity of fenobam, coupled with its robust anxiolytic activity and reported efficacy in man 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.

Key words: Glutamate, MPEP, anxiety, fenobam, mGlu5, receptor