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

• Published in: The Journal of pharmacology and experimental therapeutics 2005-11, Vol.315 (2), p.711-721
• Main Authors: Porter, Richard H.P., Jaeschke, Georg, Spooren, Will, Ballard, Theresa M., Büttelmann, Bernd, Kolczewski, Sabine, Peters, Jens-Uwe, Prinssen, Eric, Wichmann, Jürgen, Vieira, Eric, Mühlemann, Andreas, Gatti, Silvia, Mutel, Vincent, Malherbe, Pari
• Format: Article
• Language: English
• Subjects: Animals; Anti-Anxiety Agents - pharmacology; Cell Line; Cells, Cultured; CHO Cells; Conditioning, Operant - drug effects; Conflict (Psychology); Cricetinae; Cyclic AMP - metabolism; DNA, Complementary - biosynthesis; DNA, Complementary - genetics; Drinking Behavior - drug effects; Emotions - drug effects; Fever - physiopathology; Guanosine 5'-O-(3-Thiotriphosphate) - metabolism; Humans; Imidazoles - pharmacology; Inositol Phosphates - metabolism; Male; Mice; Plasmids - genetics; Pyridines - pharmacology; Rats; Rats, Sprague-Dawley; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate - agonists; Receptors, Metabotropic Glutamate - antagonists & inhibitors; Stress, Physiological - physiopathology
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.105.089839

Fenobam [N-(3-chlorophenyl)-N′-(4,5-dihydro-1-methyl-4-oxo-1 H-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.