Behavioral pharmacological profile of CGS 9895: A novel anxiomodulator with selective benzodiazepine agonist and antagonist properties

Bennett, Debra A.; Amrick, Caryl L.; Wilson, Douglas E.; Bernard, Patrick S.; Yokoyama, Naokata; Liebman, Jeffrey M.

doi:10.1002/ddr.430060404

Cited by 37 publications

(6 citation statements)

References 16 publications

(6 reference statements)

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“…CGS9895 has a similar profile except that, whilst its activity in models of anxiety is maintained (active in conflict tests, the plus maze, and partially active in antagonising the leptazol cue) [Yokoyama et al, 1982;Bennett et al, 19851, its anticonvulsant activity is limited to inconsistent antagonism of leptazol seizures and partial antagonism of audiogenic seizures in DBAz mice [Yokoyama et al, 1982;Brown et al, 1984;Bennett et al, 1985;Bernard et al, 1985b;Katzman and Shannon, 19851. Again, in tests in which CGS9895 has little or no activity alone, the effects of diazepam were antagonised (leptazol and audiogenic seizures and rotarod) [Brown et al, 1984;Bennett et al, 1985;Bernard et al, 1985b;Katzman and Shannon, 19851. Recently the 2-(5-methyl thien-3-yl) analogue S-135 ( Fig. 4) has been synthesised and has a high affinity for benzodiazepine receptors in vitro and inverse agonist properties after oral administration [Matsushita et al, 19861.…”

Section: Pyrazole[43-c]quinolone-3-(5h)-onementioning

confidence: 99%

Pharmacological profiles in vivo of benzodiazepine receptor ligands

Gardner¹

1988

Drug Development Research

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Since the discovery of specific binding sites for benzodiazepines in the brain, a range of compounds have been discovered that do not have the benzodiazepine structure but that do interact with the benzodiazepine receptors. Classical benzodiazepines were considered to be agonists at these receptors. Some compounds only possess part of the profile of classical benzodiazepines and antagonise benzodiazepines in those test procedures in which they are totally inactive. Such compounds are regarded as partial agonists. The discovery of methyl and ethyl β‐carboline‐3‐carboxylate opened a new vista in the pharmacology of benzodiazepine receptors. These agents and now several other compounds act on the benzodiazepine receptors to induce effects functionally opposite to those of classical benzodiazepines (proconvulsant and convulsant) and have been called inverse agonists. Both agonists and inverse agonists can be blocked by compounds with affinity for the receptors but little intrinsic activity (antagonists). A recent increase in the number of benzodiazepine receptor ligands with in vivo activities allows comparison of a range of compounds from several different structral groups. Their pharmacological profiles suggest that these compounds all fit onto a continuum of behavioural effects related to activation of benzodiazepine receptors.

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Section: Pyrazole[43-c]quinolone-3-(5h)-onementioning

confidence: 99%

Pharmacological profiles in vivo of benzodiazepine receptor ligands

Gardner¹

1988

Drug Development Research

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“…Residue modifications led to varying neurochemical and behavioural properties. For example, compound 1 (CGS9895; R '4 = methoxy; see Figure ) (Ramerstorfer et al, ; Varagic et al, ) not only antagonized the effects of diazepam but also showed anxiolytic and weak anticonvulsant activity while being devoid of sedation, muscle relaxation or motor impairments (Bennett et al, ; Bennett, ). These findings encouraged the possibility of separately eliciting only specific desired BZD‐like effects (Kolata, ).…”

Section: Introductionmentioning

confidence: 99%

Towards functional selectivity for α6β3γ2 GABA_A receptors: a series of novel pyrazoloquinolinones

Treven

Siebert

Holzinger

et al. 2017

British J Pharmacology

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Background and PurposeThe GABAA receptors are ligand‐gated ion channels, which play an important role in neurotransmission. Their variety of binding sites serves as an appealing target for many clinically relevant drugs. Here, we explored the functional selectivity of modulatory effects at specific extracellular α+/β− interfaces, using a systematically varied series of pyrazoloquinolinones.Experimental ApproachRecombinant GABAA receptors were expressed in Xenopus laevis oocytes and modulatory effects on GABA‐elicited currents by the newly synthesized and reference compounds were investigated by the two‐electrode voltage clamp method.Key ResultsWe identified a new compound which, to the best of our knowledge, shows the highest functional selectivity for positive modulation at α6β3γ2 GABAA receptors with nearly no residual activity at the other αxβ3γ2 (x = 1–5) subtypes. This modulation was independent of affinity for α+/γ− interfaces. Furthermore, we demonstrated for the first time a compound that elicits a negative modulation at specific extracellular α+/β− interfaces.Conclusion and ImplicationsThese results constitute a major step towards a potential selective positive modulation of certain α6‐containing GABAA receptors, which might be useful to elicit their physiological role. Furthermore, these studies pave the way towards insights into molecular principles that drive positive versus negative allosteric modulation of specific GABAA receptor isoforms.

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“…Many antidepressants downregulate either 5-HT2 receptor numbers or responsiveness following chronic administration [Peroutka and Snyder 1980;Paul et al, 19881. The anxiolytic effects of 5-HT2 antagonists have been demonstrated in clinical studies [Ceulemans et al, 1985;Reyntjens et al, 19861 and in animal models [Bennett et al, 1989;Stutzman et al, 19911. Agonists at the S-HT,, receptor, which exhibit clinically significant anxiolytic activity, potently antagonize 5-HT2 receptor mediated effects [Arnt and Hytell, 19891.…”

Section: Introductionmentioning

confidence: 94%

Mianserin‐induced 5‐HT₂ receptor downregulation results in anxiolytic effects in the elevated plus‐maze test

Benjamin

Saiff

Nevins

et al. 1992

Drug Development Research

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Benjamin, D., E.I. Saiff, T. Nevins, and H. Lal: Mianserin-induced 5-HT2 receptor downregulation results in anxiolytic effects in the elevated plus-maze test. Drug Dev. Res. 26~287-297, 1992. Several agents that downregulate 5-Hl-2 receptors produce anxiolytic effects in humans, but the role of 5-HT2 receptor downregulation has been difficult to assess because of their other actions. To test the effects of pharmacological downregulation of 5-HT2 receptors on exploratory behavior in the mouse, mianserin, a drug known to downregulate 5-HT2 receptors after a single dose, was administered 30 min, 48 hr, or 18 days prior to testing in the elevated plus-maze. Following testing in the elevated maze, the head-shake response to 4-iodo-R-( -)-2,5-dimethoxyphenylisopropylamine (DOI), a selective 5-HT,/5-HTlc agonist was assessed, and in a separate group of animals 5-HTlA, 5-HT1,, 5-HTl ,, p1,p2, and 5-HT2 agonist and antagonist binding was quantified autoradiographically. Mianserin pretreatment resulted in a significant dose-related anxiolytic effect in the elevated plus maze evidenced by increases in the percentage of entries to, and time spent on the open arms. Head-shakes induced by DO1 were also dose-dependently decreased as a result of mianserin pretreatment. At this time, the binding of the 5-HT, receptor antagonist, 7-amino-8 ['251]ketanserin was decreased by 50%. Binding of DO1 to 5-HT, receptors was decreased by 46%, and to 5-HT,c receptors was decreased by 53%, but no other changes were found in any of the other receptor types examined. These findings demonstrate that the 5-HT2 receptor plays at least a permissive role in anxiety-like behaviors, since an intact 5-HT, system is necessary for the full expression of the anxiety-like response, but the role of

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Behavioral pharmacological profile of CGS 9895: A novel anxiomodulator with selective benzodiazepine agonist and antagonist properties

Cited by 37 publications

References 16 publications

Pharmacological profiles in vivo of benzodiazepine receptor ligands

Pharmacological profiles in vivo of benzodiazepine receptor ligands

Towards functional selectivity for α6β3γ2 GABA_A receptors: a series of novel pyrazoloquinolinones

Mianserin‐induced 5‐HT₂ receptor downregulation results in anxiolytic effects in the elevated plus‐maze test

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Behavioral pharmacological profile of CGS 9895: A novel anxiomodulator with selective benzodiazepine agonist and antagonist properties

Cited by 37 publications

References 16 publications

Pharmacological profiles in vivo of benzodiazepine receptor ligands

Pharmacological profiles in vivo of benzodiazepine receptor ligands

Towards functional selectivity for α6β3γ2 GABAA receptors: a series of novel pyrazoloquinolinones

Mianserin‐induced 5‐HT2 receptor downregulation results in anxiolytic effects in the elevated plus‐maze test

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Towards functional selectivity for α6β3γ2 GABA_A receptors: a series of novel pyrazoloquinolinones

Mianserin‐induced 5‐HT₂ receptor downregulation results in anxiolytic effects in the elevated plus‐maze test