title: Fenobam: a clinically validated nonbenzodiazepine anxiolytic is a potent, selective, and noncompetitive 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 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 IC(50) = 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 IC(50) = 84 +/- 13 nM. [(3)H]Fenobam bound to rat and human recombinant receptors with K(d) values of 54 +/- 6 and 31 +/- 4 nM, respectively. MPEP inhibited [(3)H]fenobam binding to human mGlu5 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 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.
authors.affiliation: Pharma Division, Discovery Research CNS, F. Hoffmann-La Roche, Basel, Switzerland. richard.porter@roche.com
authors.forename: Richard H P
authors.initials: RH
authors.lastname: Porter
authors.forename: Georg
authors.initials: G
authors.lastname: Jaeschke
authors.forename: Will
authors.initials: W
authors.lastname: Spooren
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Ballard
authors.forename: Bernd
authors.initials: B
authors.lastname: Büttelmann
authors.forename: Sabine
authors.initials: S
authors.lastname: Kolczewski
authors.forename: Jens-Uwe
authors.initials: JU
authors.lastname: Peters
authors.forename: Eric
authors.initials: E
authors.lastname: Prinssen
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wichmann
authors.forename: Eric
authors.initials: E
authors.lastname: Vieira
authors.forename: Andreas
authors.initials: A
authors.lastname: Mühlemann
authors.forename: Silvia
authors.initials: S
authors.lastname: Gatti
authors.forename: Vincent
authors.initials: V
authors.lastname: Mutel
authors.forename: Pari
authors.initials: P
authors.lastname: Malherbe
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D016466:CHO Cells; D002460:Cell Line; D002478:Cells, Cultured; D003216:Conditioning, Operant / Q000187:drug effects; D003220:Conflict, Psychological; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004327:Drinking Behavior / Q000187:drug effects; D004644:Emotions / Q000187:drug effects; D005334:Fever / Q000503:physiopathology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007295:Inositol Phosphates / Q000378:metabolism; D008297:Male; D051379:Mice; D010957:Plasmids / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000037:antagonists & inhibitors*; D013312:Stress, Physiological / Q000503:physiopathology
chemical_list: D014151:Anti-Anxiety Agents; D018076:DNA, Complementary; D007093:Imidazoles; D007295:Inositol Phosphates; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C032794:fenobam; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C121465:6-methyl-2-(phenylethynyl)pyridine; D000242:Cyclic AMP