Novel anxiolytics that act as partial agonists at benzodiazepine receptors

Haefely, W.; Martin, James R.; Schoch, Peter

doi:10.1016/0165-6147(90)90126-s

Cited by 246 publications

(107 citation statements)

References 15 publications

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“…It has been recently suggested that partial agonists at the BZD receptor may have advantages over the more conventional full agonists regarding both their spectrum of action and their relative tolerance/dependence-inducing potential (Haefely et al, 1990). In support of this it has been found that a number of partial agonists exhibited no significant tolerance in animal models in which conventional BZDs show varying degrees of tolerance when tested over a similar period (Boast & Gerhardt, 1987;Haigh & Feely, 1988b;Feely et al, 1989).…”

Section: Introductionsupporting

confidence: 51%

“…endowed with less intrinsic activity than a full agonist, one could speculate about the clinical efficacy of imidazenil, and other partial agonists as well. However, the well-established therapeutic use of clonazepam, which also exhibits features of a partial agonist in preclinical models of antiepileptic activity (Haefely et al, 1990), leaves open the possibility that imidazenil may also prove effective in the clinical setting as an antiepileptic agent.…”

Section: Discussionmentioning

confidence: 99%

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Lack of anticonvulsant tolerance and benzodiazepine receptor down regulation with imidazenil in rats

Zanotti¹,

Mariot²,

Contarino³

et al. 1996

British J Pharmacology

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1 Development of anticonvulsant tolerance and benzodiazepine (BZD) receptor down-regulation has been reported to occur upon chronic administration of conventional BZDs. We compared the effect of chronic treatment with imidazenil, a new BZD partial agonist, and diazepam in rats. 2 After acute administration, imidazenil was more potent though less effective than diazepam in protecting from bicuculline-induced seizure. The time-course analysis of two peak equieffective doses of imidazenil (2.5 yumol kg -' p.o.) and diazepam (35 umol kg-l, p.o.) showed a longer lasting action of the former drug. 7 These data indicate that imidazenil possesses a very low tolerance potential to its anticonvulsant activity and does not affect BZD receptor density even after prolonged administration.

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Section: Introductionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Lack of anticonvulsant tolerance and benzodiazepine receptor down regulation with imidazenil in rats

Zanotti¹,

Mariot²,

Contarino³

et al. 1996

British J Pharmacology

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“…Overall, the profile displayed by the nonselective GABA Abenzodiazepine receptor partial agonists in the Mouse Defense Test Battery suggests a weak potential of these drugs in anxiety disorders. Although these compounds have been available for some time (Haefely et al, 1990) and a few clinical trials with such agents have been carried out, little is known of their efficacy in the treatment of anxiety disorders (Potokar and Nutt, 1994). It can be speculated that clinical results with these drugs were not disclosed because of their failure to show anxiolytic-like activity, thereby corroborating the findings from the Mouse Defense Test Battery.…”

Section: Effects Of Nonselective Gaba a -Benzodiazepine Receptor Ligamentioning

confidence: 99%

The Mouse Defense Test Battery: pharmacological and behavioral assays for anxiety and panic

Blanchard

Griebel

Blanchard

2003

European Journal of Pharmacology

258

159

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The Mouse Defense Test Battery was developed from tests of defensive behaviors in rats, reflecting earlier studies of both acute and chronic responses of laboratory and wild rodents to threatening stimuli and situations. It measures flight, freezing, defensive threat and attack, and risk assessment in response to an unconditioned predator stimulus, as well as pretest activity and postthreat (conditioned) defensiveness to the test context. Factor analyses of these indicate four factors relating to cognitive and emotional aspects of defense, flight, and defensiveness to the test context. In the Mouse Defense Test Battery, GABA A -benzodiazepine anxiolytics produce consistent reductions in defensive threat/attack and risk assessment, while panicolytic and panicogenic drugs selectively reduce and enhance, respectively, flight. Effects of GABA A -benzodiazepine, serotonin, and neuropeptide ligands in the Mouse Defense Test Battery are reviewed. This review suggests that the Mouse Defense Test Battery is a sensitive and appropriate tool for preclinical evaluation of drugs potentially effective against defense-related disorders such as anxiety and panic. D

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“…2). Some compounds, such as bretazenil and abecarnil, exhibit an anxioselective profile in animals (17,18), but data from clinical trials do not support the anxioselectivity predicted from preclinical results (19,20). We now report that ocinaplon (DOV 273,547; 2-pyridinyl[7-(4-pyridinyl)pyrazolo[1,5-a]-pyrimidin-3-yl]methanone) fulfills both preclinical and clinical criteria for an anxioselective agent.…”

mentioning

confidence: 98%

Selective anxiolysis produced by ocinaplon, a GABA _A receptor modulator

Lippa

Czobor

Stark

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

121

103

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Benzodiazepines remain widely used for the treatment of anxiety disorders despite prominent, often limiting side effects including sedation, muscle relaxation, and ataxia. A compound producing a robust anxiolytic action comparable to benzodiazepines, but lacking these limiting side effects at therapeutic doses (an anxioselective agent), would represent an important advance in the treatment of generalized anxiety disorder, and perhaps other anxiety disorders. Here we report that the pyrazolo[1,5-a]-pyrimidine, ocinaplon, exhibits an anxioselective profile in both preclinical procedures and in patients with generalized anxiety disorder, the most common of the anxiety disorders. In rats, ocinaplon produces significant muscle relaxation, ataxia, and sedation only at doses >25-fold higher than the minimum effective dose (3.1 mg͞kg) in the Vogel ''conflict'' test. This anticonflict effect is blocked by flumazenil (Ro 15-1788), indicating that like benzodiazepines, ocinaplon produces an anxiolytic action through allosteric modulation of GABA A receptors. Nonetheless, in eight recombinant GABAA receptor isoforms expressed in Xenopus oocytes, the potency and efficacy of ocinaplon to potentiate GABA responses varied with subunit composition not only in an absolute sense, but also relative to the prototypical benzodiazepine, diazepam. In a double blind, placebo controlled clinical trial, a 2-week regimen of ocinaplon (total daily dose of 180 -240 mg) produced statistically significant reductions in the Hamilton rating scale for anxiety scores. In this study, the incidence of benzodiazepine-like side effects (e.g., sedation, dizziness) in ocinaplon-treated patients did not differ from placebo. These findings indicate that ocinaplon represents a unique approach both for the treatment and understanding of anxiety disorders.generalized anxiety disorder ͉ benzodiazepines

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Novel anxiolytics that act as partial agonists at benzodiazepine receptors

Cited by 246 publications

References 15 publications

Lack of anticonvulsant tolerance and benzodiazepine receptor down regulation with imidazenil in rats

Lack of anticonvulsant tolerance and benzodiazepine receptor down regulation with imidazenil in rats

The Mouse Defense Test Battery: pharmacological and behavioral assays for anxiety and panic

Selective anxiolysis produced by ocinaplon, a GABA _A receptor modulator

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Novel anxiolytics that act as partial agonists at benzodiazepine receptors

Cited by 246 publications

References 15 publications

Lack of anticonvulsant tolerance and benzodiazepine receptor down regulation with imidazenil in rats

Lack of anticonvulsant tolerance and benzodiazepine receptor down regulation with imidazenil in rats

The Mouse Defense Test Battery: pharmacological and behavioral assays for anxiety and panic

Selective anxiolysis produced by ocinaplon, a GABA A receptor modulator

Contact Info

Product

Resources

About

Selective anxiolysis produced by ocinaplon, a GABA _A receptor modulator