Differential antagonism of the anticonflict effects of typical and atypical anxiolytics

Patel, Jitendra; Martin, Connie; Malick, Jeffrey B.

doi:10.1016/0014-2999(82)90331-4

Cited by 79 publications

(19 citation statements)

References 6 publications

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“…Fenobam was active in a comparable dose range after oral administration in all tests (MED 10 -30 mg/kg p.o.). These data confirm the previously reported preclinical studies with fenobam (i.e., rat conflict tasks including Geller-Seifter and Vogel) (Patel et al, 1982;Goldberg et al, 1983). The data are also in line with previous findings with selective mGlu5 receptor antagonists, particularly the prototypical mGlu5 receptor antagonist MPEP (for review, see Spooren et al, 2001).…”

Section: Discussionsupporting

confidence: 91%

“…Interestingly, fenobam (McN-3377) was originally developed as a nonbenzodiazepine anxiolytic (by McNeil Laboratories, 1978, with an unknown molecular target. In preclinical studies, fenobam is reported to be active in rat models of anxiety (conflict tasks including Geller-Seifter and Vogel) (Patel et al, 1982), and this activity was not blocked by a benzodiazepine antagonist (Goldberg et al, 1983).…”

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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

295

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: Discussionsupporting

confidence: 91%

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

295

229

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“…Further support is provided by the fact that Ro 15-1788, a potent benzodiazepine-re ceptor antagonist (23), completely blocked the zopiclone stimulus at a relative low dose of 1 mg/kg. Patel et al (24) reported that the anticonflict activity of agents…”

Section: Discussionmentioning

confidence: 99%

Behavioral analysis of zopiclone on the basis of their discriminative stimulus properties in the rat.

Yamamoto

Kumasaka²,

Ueki

1989

Jpn.J.Pharmacol

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Abstract-Zopiclone is a new cyclopyrrolone derivative which exerts pharma cological activities similar to those of benzodiazepines in behavioral and biochemical studies.In order to clarify the discriminative stimulus properties of zopiclone, 8 rats were trained to discriminate the interoceptive stimulus induced by zopiclone (3.2 mg/kg, i.p.) from those of saline.Following discrimination acquisition, admin istration of zopiclone resulted in drug-appropriate responding with an ED50 of 1.3 (1.0-1.8) mg/kg.

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“…SR95195, at low non-anxiogenic doses, also reversed the anticonflict action of diazepam. Again, inverse BZD agonists and BZD antagonists have repeatedly been shown to antagonize the anxiolytic effect of BZD ligands (Bonetti et al, 1982;Patel et al, 1983). SR95195, unlike CGS8216 (Mendelson et al, 1983) failed to counteract the disinhibitory effect of pentobarbitone in the approach-avoidance conflict test in rats, suggesting a greater selectivity towards the BZD receptor.…”

Section: Discussionmentioning

confidence: 98%

A 7‐phenyl substituted triazolopyridazine has inverse agonist activity at the benzodiazepine receptor site

Biziere

Bourguignon²,

Chambón

et al. 1987

British J Pharmacology

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1 To investigate further the structural requirements for benzodiazepine (BZD) receptor ligands, we synthesized SR.95195, [7-phenyl-3-methyl-1,2,4-triazolo-(4,3-b) pyridazine], a positional isomer of the 6-phenyl-triazolo-pyridazines, which were the first non-BZD derivatives to exhibit high affinity for the BZD receptor and BZD-like activity in vivo. (EDm: 8.6 mg kg-', i.p.), but not that of pentobarbitone 15 mg kg-', i.p.5 It is concluded that SR 95195 has the pharmacological profile of an inverse BZD agonist and that displacing the phenyl from the 6-to the 7-position in the triazolopyridazine series causes a shift from agonist to inverse agonist type activity at the BZD receptor site.

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Differential antagonism of the anticonflict effects of typical and atypical anxiolytics

Cited by 79 publications

References 6 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

Behavioral analysis of zopiclone on the basis of their discriminative stimulus properties in the rat.

A 7‐phenyl substituted triazolopyridazine has inverse agonist activity at the benzodiazepine receptor site

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