In vivo determination of efficacy of pyrazoloquinolinones at the benzodiazepine receptor

Brown, ChloëL.; Martin, Ian L.; Jones, Brian; Oakley, N.R.

doi:10.1016/0014-2999(84)90200-0

Cited by 23 publications

(17 citation statements)

References 6 publications

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“…To identify further compounds possibly mediating their effects via the a1+b3-interface and to exclude effects mediated via the high affinity benzodiazepine binding site at the a+g-interface, we investigated 32 additional pyrazoloquinolinones/pyrazolopyridinones that are structurally analogous to CGS 9895 (compound 3) (Table 1), at receptors composed of a1 and b3 subunits ( Figure 1B). Three of these compounds with the prefix CGS (compounds 1, 2 and 30) have been published as high affinity benzodiazepine site ligands (Brown et al, 1984;Loo et al, 1987;Williams et al, 1989;Smith et al, 2001;Ogris et al, 2004). Nineteen other compounds have previously been generated as a series of symmetrically substituted pyrazoloquinolinones/ pyrazolopyridinones, to probe the benzodiazepine binding site of different GABAA receptor subtypes Yu et al, 1999;He, 2000).…”

Section: Many Structural Analogues Of Cgs 9895 Interact With the A+b-mentioning

confidence: 99%

Identification of novel positive allosteric modulators and null modulators at the GABA_A receptor α+β− interface

Varagić

Wimmer

Schnürch

et al. 2013

British J Pharmacology

105

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BACKGROUND AND PURPOSEGABAA receptors are the major inhibitory neurotransmitter receptors in the mammalian brain and the target of many clinically important drugs interacting with different binding sites. Recently, we demonstrated that CGS 9895 (2-(4-methoxyphenyl)-2H-pyrazolo [4,3-c]quinolin-3(5H)-one) acts as a null modulator (antagonist) at the high affinity benzodiazepine binding site, but in addition elicits a strong enhancement of GABA-induced currents via a novel drug binding site at the extracellular a+b-interface. Here, we investigated 32 structural analogues of CGS 9895 for their ability to mediate their effects via the a1+b3-interface of GABAA receptors. EXPERIMENTAL APPROACHGABAA receptors were expressed in Xenopus laevis oocytes and investigated by the two-electrode voltage clamp method. KEY RESULTSWe not only identified compounds with higher efficacy/potency than CGS 9895 for stimulating GABA-induced currents via the a1+b3-binding site, but also discovered compounds acting as null modulators at this site. Most of the compounds also acted as null modulators via the benzodiazepine binding site of GABAA receptors. But some of the positive allosteric modulators or null modulators exclusively exerted their action via the a+b-binding site. CONCLUSION AND IMPLICATIONSPyrazoloquinolinones and pyrazolopyridinones represent the first prototype of drug candidates mediating benzodiazepine like modulatory effects via the a+b-interface of GABAA receptors. The discovery of null modulators acting as inhibitors of the plus modulators provides a highly useful tool for the discovery of additional classes of compounds that can modulate GABAA receptors via this site, which may lead to novel therapeutic principles. LINKED ARTICLEThis article is accompanied by Varagic et al.,

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Section: Many Structural Analogues Of Cgs 9895 Interact With the A+b-mentioning

confidence: 99%

Identification of novel positive allosteric modulators and null modulators at the GABA_A receptor α+β− interface

Varagić

Wimmer

Schnürch

et al. 2013

British J Pharmacology

105

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“…Due to insufficient expression of a4b3 and a6b3 receptors, the effects of these compounds at a4-or a6-containing receptors could only be investigated at a4b3g2 or a6b3g2 receptors. All compounds studied here have been investigated previously for their apparent affinity for the high-affinity benzodiazepinebinding site of GABAA receptors (Brown et al, 1984;Loo et al, 1987;Williams et al, 1989;He et al, 1999;Yu et al, 1999;Smith et al, 2001;Ogris et al, 2004), see Table 1. Whereas 10 of these compounds (1, 2, 5, 6, 7, 11, 17, 20, 22 and 30) exhibited a high affinity (nM) for the benzodiazepinebinding site of various GABAA receptor subtypes, compounds 8,23,25,27,32,33, exhibited a low (300 nM-7 mM) affinity for these binding sites (Table 1).…”

Section: Effects Of A1+b3-binding Site Ligands Depend On the A Subunimentioning

confidence: 99%

Subtype selectivity of α+β− site ligands of GABA_A receptors: identification of the first highly specific positive modulators at α6β2/3γ2 receptors

Varagić

Ramerstorfer

Huang

et al. 2013

British J Pharmacology

100

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BACKGROUND AND PURPOSEGABAA receptors are the major inhibitory neurotransmitter receptors in the mammalian brain and the target of many clinically important drugs interacting with different binding sites. Recently, we demonstrated that CGS 9895 (2-(4-methoxyphenyl)-2H-pyrazolo [4,3-c]quinolin-3(5H)-one) elicits a strong and subtype-dependent enhancement of GABA-induced currents via a novel drug-binding site at extracellular ax+by-(x = 1-6, y = 1-3) interfaces. Here, we investigated 16 structural analogues of CGS 9895 for their ability to modulate GABA-induced currents of various GABAA receptor subtypes. EXPERIMENTAL APPROACHRecombinant GABAA receptor subtypes were expressed in Xenopus laevis oocytes and investigated by the two-electrode voltage clamp method. KEY RESULTSMost of the compounds investigated were able to modulate GABA-induced currents of ab and abg receptors to a comparable extent, suggesting that the effect of these drugs is not dependent on the benzodiazepine site of GABAA receptors. Steric hindrance experiments demonstrated that these compounds exert their action predominantly via the ax+by-(x = 1-6, y = 1-3) interfaces. Whereas some compounds are unselectively modulating a broad range of receptor subtypes, other compounds feature remarkable functional selectivity for the a6b3g2 receptor, or behave as null modulators at some receptor subtypes investigated. CONCLUSION AND IMPLICATIONSPyrazoloquinolinones and pyrazolopyridinones represent the first prototypes of drugs exerting benzodiazepine-like modulatory effects via the a+b-interface of GABAA receptors. The discovery of modulators with functional subtype selectivity at this class of binding sites provides a highly useful tool for the investigation of a6b2/3g2 receptor function, and may lead to novel therapeutic principles. LINKED ARTICLE

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“…Cooper 1984; Bernard et al 1985;Petrack et al 1983;Spencer and Lal 1983). It shows high affinity binding to benzodiazepine sites (Brown et al 1984;Gee and Yamamura 1982;Haefely et al 1985;Yokoyama et al 1982). Previously, we failed to detect agonistic activity of CGS 9896 in a test of feeding .…”

mentioning

confidence: 92%

Benzodiazepine-induced hyperphagia: Stereospecificity and antagonism by pyrazoloquinolines, CGS 9895 and CGS 9896

Cooper

Yerbury

1986

Psychopharmacology

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Non-deprived male rats were familiarized with a highly palatable diet until baseline consumption in a 30-min daily access period had stabilised. Stereospecificity of the hyperphagic effect of benzodiazepine receptor agonists was demonstrated using two enantiomers, the (S)-enantiomer being Ro11-3128 (methylclonazepam) and the (R)-enantiomer, Ro11-3624. The benzodiazepine receptor antagonists, Ro15-1788 and CGS 8216, reversed the hyperphagic effect of Ro11-3128. These data confirm the mediation of the hyperphagic effect of benzodiazepines by specific receptors. In further experiments, the effects of the pyrazoloquinolines CGS 9895 and CGS 9896 were examined both alone and also in combination with clonazepam. In doses of 1.25-10.0 mg/kg, neither CGS 9895 nor CGS 9896, when given alone, had a significant effect on the consumption of the palatable diet. Both, however, dose-dependently antagonised the hyperphagic effect of clonazepam. In a test of palatable food consumption, therefore, both compounds can be characterised as benzodiazepine antagonists.

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In vivo determination of efficacy of pyrazoloquinolinones at the benzodiazepine receptor

Cited by 23 publications

References 6 publications

Identification of novel positive allosteric modulators and null modulators at the GABA_A receptor α+β− interface

Identification of novel positive allosteric modulators and null modulators at the GABA_A receptor α+β− interface

Subtype selectivity of α+β− site ligands of GABA_A receptors: identification of the first highly specific positive modulators at α6β2/3γ2 receptors

Benzodiazepine-induced hyperphagia: Stereospecificity and antagonism by pyrazoloquinolines, CGS 9895 and CGS 9896

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In vivo determination of efficacy of pyrazoloquinolinones at the benzodiazepine receptor

Cited by 23 publications

References 6 publications

Identification of novel positive allosteric modulators and null modulators at the GABAA receptor α+β− interface

Identification of novel positive allosteric modulators and null modulators at the GABAA receptor α+β− interface

Subtype selectivity of α+β− site ligands of GABAA receptors: identification of the first highly specific positive modulators at α6β2/3γ2 receptors

Benzodiazepine-induced hyperphagia: Stereospecificity and antagonism by pyrazoloquinolines, CGS 9895 and CGS 9896

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Identification of novel positive allosteric modulators and null modulators at the GABA_A receptor α+β− interface

Identification of novel positive allosteric modulators and null modulators at the GABA_A receptor α+β− interface

Subtype selectivity of α+β− site ligands of GABA_A receptors: identification of the first highly specific positive modulators at α6β2/3γ2 receptors