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Barbiturates allosterically inhibit GABA antagonist and benzodiazepine inverse agonist binding

Wong, Erik H F ; Snowman, Adele M. ; Fredrik Leeb-Lundberg, L. M. LU and Olsen, Richard W. (1984) In European Journal of Pharmacology 102(2). p.205-212
Abstract

Barbiturates and the related depressant drugs, etazolate and etomidate, inhibited both the binding of [3H]bicuculline methochloride (BMC) to γ-aminobutyric acid (GABA) receptor sites and the binding of [3H]β-carboline-3-carboxylic acid methyl ester (βCCM) to benzodiazepine receptor sites in mammalian brain. These concentration-dependent effects were chemically specific and stereospecific in a manner correlating with the activity of barbiturates to enhance GABA responses in neurons and to enhance GABA and benzodiazepine receptor agonist binding in vitro. The barbiturate inhibition of [3H]BMC binding involved a decrease in affinity which at high concentrations of barbiturates results in an effective... (More)

Barbiturates and the related depressant drugs, etazolate and etomidate, inhibited both the binding of [3H]bicuculline methochloride (BMC) to γ-aminobutyric acid (GABA) receptor sites and the binding of [3H]β-carboline-3-carboxylic acid methyl ester (βCCM) to benzodiazepine receptor sites in mammalian brain. These concentration-dependent effects were chemically specific and stereospecific in a manner correlating with the activity of barbiturates to enhance GABA responses in neurons and to enhance GABA and benzodiazepine receptor agonist binding in vitro. The barbiturate inhibition of [3H]BMC binding involved a decrease in affinity which at high concentrations of barbiturates results in an effective complete loss of detectable binding. The maximal inhibition of [3H]βCCM binding involved a more modest decrease in affinity (increase in KD from 1.35 to 1.85 nM). The barbiturate inhibitions of both ligands could be reversed by picrotoxin, suggesting an indirect action at previously defined picrotoxin/barbiturate modulatory sites on the GABA-benzodiazepine receptor/chloride ion channel complex.

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author
; ; and
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Barbiturates, Benzodiapines, Chloride ion channels, CNS depressants, GABA receptors
in
European Journal of Pharmacology
volume
102
issue
2
pages
205 - 212
publisher
Elsevier
external identifiers
  • scopus:0021272349
  • pmid:6090160
ISSN
0014-2999
DOI
10.1016/0014-2999(84)90252-8
language
English
LU publication?
no
id
d8e283c5-7b08-407a-a133-f41486380fe7
date added to LUP
2019-06-12 11:50:18
date last changed
2024-01-01 09:54:00
@article{d8e283c5-7b08-407a-a133-f41486380fe7,
  abstract     = {{<p>Barbiturates and the related depressant drugs, etazolate and etomidate, inhibited both the binding of [<sup>3</sup>H]bicuculline methochloride (BMC) to γ-aminobutyric acid (GABA) receptor sites and the binding of [<sup>3</sup>H]β-carboline-3-carboxylic acid methyl ester (βCCM) to benzodiazepine receptor sites in mammalian brain. These concentration-dependent effects were chemically specific and stereospecific in a manner correlating with the activity of barbiturates to enhance GABA responses in neurons and to enhance GABA and benzodiazepine receptor agonist binding in vitro. The barbiturate inhibition of [<sup>3</sup>H]BMC binding involved a decrease in affinity which at high concentrations of barbiturates results in an effective complete loss of detectable binding. The maximal inhibition of [<sup>3</sup>H]βCCM binding involved a more modest decrease in affinity (increase in K<sub>D</sub> from 1.35 to 1.85 nM). The barbiturate inhibitions of both ligands could be reversed by picrotoxin, suggesting an indirect action at previously defined picrotoxin/barbiturate modulatory sites on the GABA-benzodiazepine receptor/chloride ion channel complex.</p>}},
  author       = {{Wong, Erik H F and Snowman, Adele M. and Fredrik Leeb-Lundberg, L. M. and Olsen, Richard W.}},
  issn         = {{0014-2999}},
  keywords     = {{Barbiturates; Benzodiapines; Chloride ion channels; CNS depressants; GABA receptors}},
  language     = {{eng}},
  month        = {{07}},
  number       = {{2}},
  pages        = {{205--212}},
  publisher    = {{Elsevier}},
  series       = {{European Journal of Pharmacology}},
  title        = {{Barbiturates allosterically inhibit GABA antagonist and benzodiazepine inverse agonist binding}},
  url          = {{http://dx.doi.org/10.1016/0014-2999(84)90252-8}},
  doi          = {{10.1016/0014-2999(84)90252-8}},
  volume       = {{102}},
  year         = {{1984}},
}