A synthetic non-benzodiazepine ligand for benzodiazepine receptors: A probe for investigating neuronal substrates of anxiety

Lippa, Arnold S.; Coupet, Joseph; Greenblatt, E. N.; Klepner, Claire A.; Beer, Bernard

doi:10.1016/0091-3057(79)90304-6

Cited by 266 publications

(46 citation statements)

References 26 publications

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“…Although the present data do not provide direct evidence that GABA A1a receptors are involved in anxiety, some support may be derived from previous reports of anxiolysis produced by agonists at ␣ 1 subunit-containing GABA A receptors, such as ocinaplon (Lippa et al, 2005) and CL 218,872 (Lippa et al, 1979), as well as reports (Cox et al, 1995;Harvey et al, 2002) that a selective antagonist at GABA A1a receptors (tert-butyl-␤-carboline carboxylate) blocks the anxiolytic but not the motor-impairing actions of benzodiazepines (Shannon et al, 1984). …”

Section: Discussioncontrasting

confidence: 38%

The Anxioselective Agent 7-(2-Chloropyridin-4-yl)pyrazolo-[1,5-a]-pyrimidin-3-yl](pyridin-2-yl)methanone (DOV 51892) Is More Efficacious Than Diazepam at Enhancing GABA-Gated Currents at α₁ Subunit-Containing GABA_A Receptors

Popik

Kostakis

Krawczyk

et al. 2006

J Pharmacol Exp Ther

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Studies using mice with point mutations of GABA A receptor ␣ subunits suggest that the sedative and anxiolytic properties of 1,4-benzodiazepines are mediated, respectively, by GABA A receptors bearing the ␣ 1 and ␣ 2 subunits. This hypothesis predicts that a compound with high efficacy at GABA A receptors containing the ␣ 1 subunit would produce sedation, whereas an agonist acting at ␣ 2 subunit-containing receptors (with low or null efficacy at ␣ 1 -containing receptors) would be anxioselective. Electrophysiological studies using recombinant GABA A receptors expressed in Xenopus oocytes indicate that maximal potentiation of GABA-stimulated currents by the pyrazolo-[1,5-a]-pyrimidine, DOV 51892, at ␣ 1 ␤ 2 ␥ 2S constructs of the GABA A receptor was significantly higher (148%) than diazepam. In contrast, DOV 51892 was considerably less efficacious and/or potent than diazepam in enhancing GABA-stimulated currents mediated by constructs containing ␣ 2 , ␣ 3 , or ␣ 5 subunits. In vivo, DOV 51892 increased punished responding in the Vogel conflict test, an effect blocked by flumazenil, and increased the percentage of time spent in the open arms of the elevated plus-maze. However, DOV 51892 had no consistent effects on motor function or muscle relaxation at doses more than 1 order of magnitude greater than the minimal effective anxiolytic dose. Although the mutant mouse data predict that the high-efficacy potentiation of GABA A1a receptor-mediated currents by DOV 51892 would be sedating, behavioral studies demonstrate that DOV 51892 is anxioselective, indicating that GABA potentiation mediated by ␣ 1 subunit-containing GABA A receptors may be neither the sole mechanism nor highly predictive of the sedative properties of benzodiazepine recognition site modulators.

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Section: Discussioncontrasting

confidence: 38%

The Anxioselective Agent 7-(2-Chloropyridin-4-yl)pyrazolo-[1,5-a]-pyrimidin-3-yl](pyridin-2-yl)methanone (DOV 51892) Is More Efficacious Than Diazepam at Enhancing GABA-Gated Currents at α₁ Subunit-Containing GABA_A Receptors

Popik

Kostakis

Krawczyk

et al. 2006

J Pharmacol Exp Ther

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“…It has been suggested that these compounds have affinities for the benzodiazepine receptors of the cerebellum that are different from those for the cerebral cortex receptors and that they have good separation ratios between their anxiolytic action and side effects. However, it is difficult to explain the relation between the pharmacologic effects and the sites of binding of CL21 8872 (21), as this compound showed a higher affinity for the benzodiazepine receptors in the cerebellum than those in other regions of the brain, but had reduced muscle-relaxant action. Also, it is presently unclear whether the modes of CGS9896 binding differ between the cerebellum and forebrain.…”

Section: Discussionmentioning

confidence: 99%

Pharmacologic characterization of a novel non-benzodiazepine selective anxiolytic, DN-2327.

et al. 1989

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“…(2) The second approach was based on the recognition that GABA A receptors are divided into subtypes which dier in their subunit composition and regional distribution in the brain (for review, see MoÈ hler, 2000;MoÈ hler et al, 2000). The triazolopyridazine CL218872 was the ®rst ligand which displayed a dierential anity for the benzodiazepine site, since it displaced [ 3 H]-diazepam with higher anity from cerebellar than from hippocampal or cortical membranes (Lippa et al, 1979). The hypnotic zolpidem, an imidazopyridine, was the ®rst subtypeselective ligand in clinical use.…”

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confidence: 99%

Mechanism of action of the hypnotic zolpidem in vivo

Crestani¹,

Martin²,

Möhler³

et al. 2000

British J Pharmacology

280

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Zolpidem is a widely used hypnotic agent acting at the GABA A receptor benzodiazepine site. On recombinant receptors, zolpidem displays a high anity to a1-GABA A receptors, an intermediate anity to a 2 -and a 3 -GABA A receptors and fails to bind to a 5 -GABA A receptors. However, it is not known which receptor subtype is essential for mediating the sedative-hypnotic action in vivo. Studying a1(H101R) mice, which possess zolpidem-insensitive a 1 -GABA A receptors, we show that the sedative action of zolpidem is exclusively mediated by a 1 -GABA A receptors. Similarly, the activity of zolpidem against pentylenetetrazole-induced tonic convulsions is also completely mediated by a 1 -GABA A receptors. These results establish that the sedative-hypnotic and anticonvulsant activities of zolpidem are due to its action on a 1 -GABA A receptors and not on a 2 -or a 3 -GABA A receptors.

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A synthetic non-benzodiazepine ligand for benzodiazepine receptors: A probe for investigating neuronal substrates of anxiety

Cited by 266 publications

References 26 publications

The Anxioselective Agent 7-(2-Chloropyridin-4-yl)pyrazolo-[1,5-a]-pyrimidin-3-yl](pyridin-2-yl)methanone (DOV 51892) Is More Efficacious Than Diazepam at Enhancing GABA-Gated Currents at α₁ Subunit-Containing GABA_A Receptors

The Anxioselective Agent 7-(2-Chloropyridin-4-yl)pyrazolo-[1,5-a]-pyrimidin-3-yl](pyridin-2-yl)methanone (DOV 51892) Is More Efficacious Than Diazepam at Enhancing GABA-Gated Currents at α₁ Subunit-Containing GABA_A Receptors

Pharmacologic characterization of a novel non-benzodiazepine selective anxiolytic, DN-2327.

Mechanism of action of the hypnotic zolpidem in vivo

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A synthetic non-benzodiazepine ligand for benzodiazepine receptors: A probe for investigating neuronal substrates of anxiety

Cited by 266 publications

References 26 publications

The Anxioselective Agent 7-(2-Chloropyridin-4-yl)pyrazolo-[1,5-a]-pyrimidin-3-yl](pyridin-2-yl)methanone (DOV 51892) Is More Efficacious Than Diazepam at Enhancing GABA-Gated Currents at α1 Subunit-Containing GABAA Receptors

The Anxioselective Agent 7-(2-Chloropyridin-4-yl)pyrazolo-[1,5-a]-pyrimidin-3-yl](pyridin-2-yl)methanone (DOV 51892) Is More Efficacious Than Diazepam at Enhancing GABA-Gated Currents at α1 Subunit-Containing GABAA Receptors

Pharmacologic characterization of a novel non-benzodiazepine selective anxiolytic, DN-2327.

Mechanism of action of the hypnotic zolpidem in vivo

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The Anxioselective Agent 7-(2-Chloropyridin-4-yl)pyrazolo-[1,5-a]-pyrimidin-3-yl](pyridin-2-yl)methanone (DOV 51892) Is More Efficacious Than Diazepam at Enhancing GABA-Gated Currents at α₁ Subunit-Containing GABA_A Receptors

The Anxioselective Agent 7-(2-Chloropyridin-4-yl)pyrazolo-[1,5-a]-pyrimidin-3-yl](pyridin-2-yl)methanone (DOV 51892) Is More Efficacious Than Diazepam at Enhancing GABA-Gated Currents at α₁ Subunit-Containing GABA_A Receptors