Fenobam: a clinically validated nonbenzodiazepine anxiolytic is a potent, selective, and noncompetitive mGlu5 receptor antagonist with inverse agonist activity.
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.
Porter
Richard H P
RH
Pharma Division, Discovery Research CNS, F. Hoffmann-La Roche, Basel, Switzerland. richard.porter@roche.com
Jaeschke
Georg
G
Spooren
Will
W
Ballard
Theresa M
TM
Büttelmann
Bernd
B
Kolczewski
Sabine
S
Peters
Jens-Uwe
JU
Prinssen
Eric
E
Wichmann
Jürgen
J
Vieira
Eric
E
Mühlemann
Andreas
A
Gatti
Silvia
S
Mutel
Vincent
V
Malherbe
Pari
P
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
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