In Vitro and in Vivo Metabolism of the Antianxiolytic Agent Fenobam in the Rat

doi:10.1002/jps.2600840212

Journal of Pharmaceutical Sciences

Volume 84, Issue 2, February 1995, Pages 185-189

https://doi.org/10.1002/jps.2600840212 Get rights and content

Abstract

Fenobam [(Fn); N‐(3‐chlorophenyl)‐N‐(4,5‐dihydro‐1‐methyl‐4‐oxo‐1H‐imidazole‐2‐yl)urea] sulfate is a novel agent with potent anxiolytic activity in rats. [¹⁴C]Fn sulfate was administered as an oral solution (250 mg/kg) to male Wistar rats, and 52% of the administered dose was excreted in urine (0–5 days). In vitro metabolism of Fn was studied by incubating [¹⁴C]Fn with rat hepatic 9000 × g supernatant preparations. Unchanged Fn and a total of six metabolites were isolated, quantified, and identified from the urine and liver 9000 × g supernatant samples by column chromatography; TLC; UV, IR, and NMR spectroscopy; MS; and comparison with synthetic samples. Four metabolic pathways for Fn are proposed: (1) hydroxylation at the phenyl ring to form 4‐hydroxyphenyl‐Fn, a major pathway in vivo (12% of the sample radioactivity) but a minor pathway in vitro (4% of the sample radioactivity); (2) hydroxylation at the creatinine ring to form (5‐hydroxy‐Fn (19%) of the sample radioactivity), a dominant pathway in vitro but not in vivo; (3) oxidative cleavage at the creatinine ring (loss of a ketene unit), a minor pathway for Fn but an important pathway for 4‐hydroxyphenyl‐Fn in vivo; and (4) N‐demythylation, a minor pathway for Fn in vivo.

References and Notes (12)

J.B. Patel et al.
Eur. J. Pharmacol.
(1982)
M.E. Goldberg et al.
Neuropharmacology
(1983)
C.R. Rasmussen et al.
Abstracts, 178th ACS National Meeting
Division of Medicinal Chemistry Abstrac
(1979)
C.R. Rasmussen
U.S. Patent
(1976)
F.L. Fabre
Clin. Res.
(1977)
T.M. Itil et al.
Curr. Ther. Res. Clin. Exp.
(1978)

There are more references available in the full text version of this article.

Cited by (17)

Effect of Novel Allosteric Modulators of Metabotropic Glutamate Receptors on Drug Self-administration and Relapse: A Review of Preclinical Studies and Their Clinical Implications
2018, Biological Psychiatry
Citation Excerpt :
MFZ 10-7 had no effect on locomotion but decreased sucrose self-administration. Using similar procedures, Keck et al. (67) also assessed the effect of fenobam sulfate (McN-3377) (74), which had originally been developed as a nonbenzodiazepine anxiolytic by McNeil Laboratories and was subsequently discovered to be a selective NAM of mGluR5 (75). The effects of fenobam were similar to effects of MFZ 10-7: decreased cocaine and sucrose self-administration without change in locomotion.
Results from preclinical rodent studies during the last 20 years implicated glutamate neurotransmission in different brain regions in drug self-administration and rodent models of relapse. These results, along with evidence for drug-induced neuroadaptations in glutamatergic neurons and receptors, suggested that addiction might be treatable by medications that inhibit glutamatergic responses to drugs of abuse, drug-associated cues, and stressors. This idea is supported by findings in rodent and primate models that drug self-administration and relapse are reduced by systemic injections of antagonists of ionotropic glutamate receptors or metabotropic glutamate receptors (mGluRs) or orthosteric agonists of mGluR2/3. However, these compounds have not advanced to clinical use because of potential side effects and other factors. This state of affairs has led to the development of positive allosteric modulators (PAMs) and negative allosteric modulators (NAMs) of mGluRs. PAMs and NAMs of mGluRs, either of which can inhibit evoked glutamate release, may be suitable for testing in humans. We reviewed results from recent studies of systemically injected PAMs and NAMs of mGluRs in rodents and monkeys, focusing on whether they reduce drug self-administration, reinstatement of drug seeking, and incubation of drug craving. We also review results from rat studies in which PAMs or NAMs of mGluRs were injected intracranially to reduce drug self-administration and reinstatement. We conclude that PAMs and NAMs of mGluRs should be considered for clinical trials.
The anxiolytic and analgesic properties of fenobam, a potent mGlu5 receptor antagonist, in relation to the impairment of learning
2009, Neuropharmacology
Citation Excerpt :
No clear PK–PD relationship was obtained in that study. A similar conclusion was obtained by a more recent pharmacokinetic analysis, which showed that fenobam levels were dose-dependent but variable, with mean peak levels of 39.7 ± 18.4 ng/ml recorded at 180 min after the 150 mg dose (Berry-Kravis et al., 2009) Indeed, the currently available data indicate that fenobam is intensively metabolized by rats (Wu et al., 1995; Wu and McKown, 2000). All of the tests used in the present investigation have been validated with reference substances and the results have been provided here or in our previous publications, as listed in Table 1.
Fenobam [N-(3-chlorophenyl)-N′-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea] was suggested to possess anxiolytic actions 30 years ago. Hoffmann-La Roche researchers recently reported that it is a selective and potent mGlu5 receptor antagonist, acting as a negative allosteric modulator. In the present study, we show that fenobam readily penetrates to the brain, reaching concentrations over 600 nM, clearly above the affinity for mGluR5 receptors. Fenobam (at 10, 30, and 100 mg/kg) did not affect horizontal locomotor activity in the open field test. Anxiolytic-like activity in the context freezing test was seen at 30 mg/kg, while fenobam was not active in the elevated plus maze test at the tested concentrations. Fenobam had antinociceptive actions in the formalin test at 10 and 30 mg/kg, but failed to attenuate mechanical allodynia in the chronic constriction injury model. Impairment of learning was revealed in the passive avoidance test at 30 mg/kg. Fenobam also impaired performance in both the Morris water maze and in the contextual fear conditioning test at the doses of 30 and 10 mg/kg, respectively. Prepulse inhibition, used as a model of psychomimetic activity, was not affected by fenobam at doses of up to 60 mg/kg. Our results indicate that the beneficial effects of fenobam occur in a similar dose range as the potential side-effects.
Synthesis and biological evaluation of fenobam analogs as mGlu5 receptor antagonists
2007, Bioorganic and Medicinal Chemistry Letters
Rational design, synthesis, and structure-activity relationship of benzoxazolones: New potent mglu5 receptor antagonists based on the fenobam structure
2007, Bioorganic and Medicinal Chemistry Letters
Phenyl ureas of creatinine as mGluR5 antagonists. A structure-activity relationship study of fenobam analogues
2006, Bioorganic and Medicinal Chemistry Letters
Fenobam (1) was developed by McNeil Laboratories as an anxiolytic agent with an unknown molecular target in the late 1970s. In a recent publication, it was revealed that fenobam is a non-competitive mGluR5 antagonist. Herein, we present the structure–activity relationship of fenobam and its analogues and similarities between the SAR of mGluR5 antagonism and the SAR of CNS properties originally reported by McNeil are discussed.
Sleep and diurnal rest-activity rhythm disturbances in a mouse model of Alzheimer's disease
2020, Sleep

View all citing articles on Scopus

View full text

Research ArticlesIn Vitro and in Vivo Metabolism of the Antianxiolytic Agent Fenobam in the Rat

Abstract

Eur. J. Pharmacol.

Neuropharmacology

Abstracts, 178th ACS National Meeting

Division of Medicinal Chemistry Abstrac

U.S. Patent

Clin. Res.

Curr. Ther. Res. Clin. Exp.

Research Articles
In Vitro and in Vivo Metabolism of the Antianxiolytic Agent Fenobam in the Rat