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

Wu, Wenhua; McKown, Linda A.; O’Neill, Patrick J.

doi:10.1002/jps.2600840212

Cited by 18 publications

(10 citation statements)

References 3 publications

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“…Interestingly, analogs of fenobam (Hunkeler and Kyburz, 1980) or the more structurally diverse mGlu5 receptor antagonists MPEP and MTEP do not cause the same behavioral disruption as fenobam in animals. Consequently, we cannot rule out an additional site of action of fenobam or possibly the formation of a biologically active metabolite because fenobam is extensively metabolized in vivo (Wu et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

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

Porter

Jaeschke²,

Spooren³

et al. 2005

J Pharmacol Exp Ther

291

229

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Fenobam [N-(3-chlorophenyl)-NЈ-(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 ϭ 58 Ϯ 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 ϭ 84 Ϯ

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Section: Discussionmentioning

confidence: 99%

“…However, fenobam has also been reported to be inactive in one phase II outpatient trial where side effects of a psychostimulant nature were reported (Friedmann et al, 1980). At the time, fenobam was discontinued from further development as an anxiolytic, with indications that the molecule required further refinement (Friedmann et al, 1980;Wu et al, 1995).…”

mentioning

confidence: 99%

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

Porter

Jaeschke²,

Spooren³

et al. 2005

J Pharmacol Exp Ther

291

229

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“…Especially for chronic in vivo experiments requiring sustained receptor blockade, the need for several daily drug administrations presents logistical challenges, can confound phenotypes of animal models and behavioral tests, and is not feasible, e.g., when working with newborn animals or fragile transgenic mouse lines. The in vivo use of fenobam is limited by an extensive metabolism (Wu et al, 1995) leading to variable exposure and possibly producing pharmacologically active metabolites . For MPEP, a weak inhibition of the norepinephrine transporter (Heidbreder et al, 2003), weak activities on NR2B-containing NMDA receptors and monoamine oxidase A (Lea and Faden, 2006), and positive allosteric modulation of mGlu4 (Mathiesen et al, 2003) have been reported.…”

Section: Introductionmentioning

confidence: 99%

CTEP: A Novel, Potent, Long-Acting, and Orally Bioavailable Metabotropic Glutamate Receptor 5 Inhibitor

Lindemann¹,

Jaeschke²,

Michalon³

et al. 2011

J Pharmacol Exp Ther

106

127

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The metabotropic glutamate receptor 5 (mGlu5) is a glutamateactivated class C G protein-coupled receptor widely expressed in the central nervous system and clinically investigated as a drug target for a range of indications, including depression, Parkinson's disease, and fragile X syndrome. Here, we present the novel potent, selective, and orally bioavailable mGlu5 negative allosteric modulator with inverse agonist properties 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine (CTEP). CTEP binds mGlu5 with low nanomolar affinity and shows Ͼ1000-fold selectivity when tested against 103 targets, including all known mGlu receptors. CTEP penetrates the brain with a brain/plasma ratio of 2.6 and displaces the tracer [ 3 H]3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-methyl-oxime (ABP688) in vivo in mice from brain regions expressing mGlu5 with an average ED 50 equivalent to a drug concentration of 77.5 ng/g in brain tissue. This novel mGlu5 inhibitor is active in the stress-induced hyperthermia procedure in mice and the Vogel conflict drinking test in rats with minimal effective doses of 0.1 and 0.3 mg/kg, respectively, reflecting a 30-to 100-fold higher in vivo potency compared with 2-methyl-6-(phenylethynyl)pyridine (MPEP) and fenobam. CTEP is the first reported mGlu5 inhibitor with both long half-life of approximately 18 h and high oral bioavailability allowing chronic treatment with continuous receptor blockade with one dose every 48 h in adult and newborn animals. By enabling long-term treatment through a wide age range, CTEP allows the exploration of the full therapeutic potential of mGlu5 inhibitors for indications requiring chronic receptor inhibition.

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“…The brain concentration of 30 mg/kg fenobam 40 min after oral administration in adult rats reaches 600 nM, whereas its IC 50 for mGluR5 is only 58 nM [25]. Fenobam is also very rapidly metabolized in rats in vivo [41]. Therefore, the exacerbation of brain injury by i.p.…”

Section: Discussionmentioning

confidence: 99%

Effects of mGluR5 positive and negative allosteric modulators on brain damage evoked by hypoxia-ischemia in neonatal rats

Makarewicz

Słomka²,

Danysz³

et al. 2015

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A b s t r a c t In the present study, we examined the effects of negative and positive allosteric modulators of metabotropic glutamate receptor 5 (mGluR5), fenobam and ADX47273, respectively, on brain damage induced by hypoxia-ischemia (H-I) in 7-day-old rats. The test drugs were administered intraperitoneally 10 min after H-I. Rectal body temperature was measured for 2.5 h after the insult. The number of apoptotic neurons in the immature rat brain was evaluated after 24 h. The wet weight of both hemispheres was determined 14 days after H-I, and its loss was used as an indicator of brain damage. In the vehicle-treated groups, H-I reduced the weight of the ipsilateral (ischemic

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

Cited by 18 publications

References 3 publications

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

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

CTEP: A Novel, Potent, Long-Acting, and Orally Bioavailable Metabotropic Glutamate Receptor 5 Inhibitor

Effects of mGluR5 positive and negative allosteric modulators on brain damage evoked by hypoxia-ischemia in neonatal rats

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