Interaction of barbiturates of various pharmacological categories with benzodiazepine receptors
(1982) In Molecular Pharmacology 21(2). p.320-328- Abstract
Numerous barbiturates, such as (±)-pentobarbital, reversibly enhance the affinity for equilibrium binding of [3H]diazepam to well-washed rat cortical membranes in a chloride-dependent and picrotoxinin-sensitive manner [Leeb-Lundberg et al., Proc. Natl. Acad. Sci. U.S.A. 77:7468-7472 (1980)]. The chemical specificity and stereospecificity of this barbiturate effect in vitro has been examined in detail for comparison with pharmacological actions of barbiturates as central nervous system depressants and modulators of inhibitory transmission mediated by γ-aminobutyric acid. One group of barbiturates, chemically and pharmacologically related to (±)-pentobarbital, such as (±)-secobarbital, (±)-dimethylbutyl barbituric acid,... (More)
Numerous barbiturates, such as (±)-pentobarbital, reversibly enhance the affinity for equilibrium binding of [3H]diazepam to well-washed rat cortical membranes in a chloride-dependent and picrotoxinin-sensitive manner [Leeb-Lundberg et al., Proc. Natl. Acad. Sci. U.S.A. 77:7468-7472 (1980)]. The chemical specificity and stereospecificity of this barbiturate effect in vitro has been examined in detail for comparison with pharmacological actions of barbiturates as central nervous system depressants and modulators of inhibitory transmission mediated by γ-aminobutyric acid. One group of barbiturates, chemically and pharmacologically related to (±)-pentobarbital, such as (±)-secobarbital, (±)-dimethylbutyl barbituric acid, (-)-dimethylbutyl barbituric acid, amobarbital, and (+)- and (-)-pentobarbital, behaved similarly in this system. These compounds enhanced [3H]diazepam binding to the same maximal level (about 125% above baseline), with EC50 values ranging from 30 to 300 μM ('full agonists'). Although (-)-isomers of pentobarbital and dimethylbutyl barbituric acid were more potent than the racemic pair, the (+)-isomer of pentobarbital was still equally efficacious. All of the active compounds in this series are nervous system depressants with anesthetic/hypnotic activity, but some of them additionally show excitatory activity in vivo. Another group of barbiturates, all with N1-methyl substitutions, showed a stereospecific enhancement of [3H]diazepam binding, but with a maximal effect lower than that of the (±)-pentobarbital series. In three cases, the isomer having more central nervous system depressant activity, (+)-hexobarbital, (-)N1-methyl, 5-phenyl, 5-propyl barbituric acid, and (-)-mephobarbital, enhanced [3H]diazepam binding, but to a maximal level varying from 35% to 75%. In addition, these agents reduced the (±)-pentobarbital enhancement down to their own maximal level, suggestive of a 'partial agonist/antagonist' action. The pharmacologically weak (-)-hexobarbital had no effect on [3H]diazepam in the absence or presence of pentobarbital, a lack of activity shared by the compound barbital. (+)-Mephobarbital and the excitatory barbiturate (+)-methyl, phenyl, propyl barbituric acid did not enhance equilibrium [3H]diazepam binding on their own, but they reversed the enhancement by (±)-pentobarbital completely and competitively. This 'antagonist' property was shared by another group of barbiturates typified by phenobarbital and (±)-metharbital. The decrease in the K(D) for the [3H]diazepam binding induced by (±)-pentobarbital was due to a saturable decrease both in the dissociation rate constant (k-1) and in the association rate constant (k1), with the effect on k-1 predominating. The K(D) values calculated from the kinetic constants measured in the absence or presence of (±)-pentobarbital were consistent with equilibrium binding parameters. The EC50 for (±)-pentobarbital to decrease k-1 was 100 μM. Phenobarbital, although inducing no apparent effect on equilibrium [3H]diazepam binding, also caused a saturable decrease in both k-1 and k1, with an EC50 on k-1 of 260 μM. However, the changes in the two rates were equal, therefore not altering the net value of K(D) for [3H]diazepam binding. Thus phenobarbital acts at the same receptor sites as pentobarbital in this in vitro system, but in a somewhat different manner. These results suggest that barbiturates can be divided into different groups depending on the type of interaction with benzodiazepine receptor binding. The qualitatively different types of interaction with [3H]diazepam binding in vitro suggest that the categories so defined might correspond to different categories of pharmacological actions of barbiturates as anesthetics, hypnotics, convulsants, anticonvulsants, or inactive. Testing this theory will require more quantitative information.
(Less)
- author
- Leeb-Lundberg, F. LU and Olsen, R. W.
- publishing date
- 1982-01-01
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Molecular Pharmacology
- volume
- 21
- issue
- 2
- pages
- 320 - 328
- publisher
- American Society for Pharmacology and Experimental Therapeutics
- external identifiers
-
- pmid:6285168
- scopus:0020004531
- ISSN
- 0026-895X
- language
- English
- LU publication?
- no
- id
- 63e5e3e4-d76a-4d40-8758-631fe02875c0
- alternative location
- http://molpharm.aspetjournals.org/content/21/2/320
- date added to LUP
- 2019-06-12 11:54:41
- date last changed
- 2024-01-01 09:55:39
@article{63e5e3e4-d76a-4d40-8758-631fe02875c0,
abstract = {{<p>Numerous barbiturates, such as (±)-pentobarbital, reversibly enhance the affinity for equilibrium binding of [<sup>3</sup>H]diazepam to well-washed rat cortical membranes in a chloride-dependent and picrotoxinin-sensitive manner [Leeb-Lundberg et al., Proc. Natl. Acad. Sci. U.S.A. 77:7468-7472 (1980)]. The chemical specificity and stereospecificity of this barbiturate effect in vitro has been examined in detail for comparison with pharmacological actions of barbiturates as central nervous system depressants and modulators of inhibitory transmission mediated by γ-aminobutyric acid. One group of barbiturates, chemically and pharmacologically related to (±)-pentobarbital, such as (±)-secobarbital, (±)-dimethylbutyl barbituric acid, (-)-dimethylbutyl barbituric acid, amobarbital, and (+)- and (-)-pentobarbital, behaved similarly in this system. These compounds enhanced [<sup>3</sup>H]diazepam binding to the same maximal level (about 125% above baseline), with EC<sub>50</sub> values ranging from 30 to 300 μM ('full agonists'). Although (-)-isomers of pentobarbital and dimethylbutyl barbituric acid were more potent than the racemic pair, the (+)-isomer of pentobarbital was still equally efficacious. All of the active compounds in this series are nervous system depressants with anesthetic/hypnotic activity, but some of them additionally show excitatory activity in vivo. Another group of barbiturates, all with N<sup>1</sup>-methyl substitutions, showed a stereospecific enhancement of [<sup>3</sup>H]diazepam binding, but with a maximal effect lower than that of the (±)-pentobarbital series. In three cases, the isomer having more central nervous system depressant activity, (+)-hexobarbital, (-)N<sup>1</sup>-methyl, 5-phenyl, 5-propyl barbituric acid, and (-)-mephobarbital, enhanced [<sup>3</sup>H]diazepam binding, but to a maximal level varying from 35% to 75%. In addition, these agents reduced the (±)-pentobarbital enhancement down to their own maximal level, suggestive of a 'partial agonist/antagonist' action. The pharmacologically weak (-)-hexobarbital had no effect on [<sup>3</sup>H]diazepam in the absence or presence of pentobarbital, a lack of activity shared by the compound barbital. (+)-Mephobarbital and the excitatory barbiturate (+)-methyl, phenyl, propyl barbituric acid did not enhance equilibrium [<sup>3</sup>H]diazepam binding on their own, but they reversed the enhancement by (±)-pentobarbital completely and competitively. This 'antagonist' property was shared by another group of barbiturates typified by phenobarbital and (±)-metharbital. The decrease in the K(D) for the [<sup>3</sup>H]diazepam binding induced by (±)-pentobarbital was due to a saturable decrease both in the dissociation rate constant (k<sub>-1</sub>) and in the association rate constant (k<sub>1</sub>), with the effect on k<sub>-1</sub> predominating. The K(D) values calculated from the kinetic constants measured in the absence or presence of (±)-pentobarbital were consistent with equilibrium binding parameters. The EC<sub>50</sub> for (±)-pentobarbital to decrease k<sub>-1</sub> was 100 μM. Phenobarbital, although inducing no apparent effect on equilibrium [<sup>3</sup>H]diazepam binding, also caused a saturable decrease in both k<sub>-1</sub> and k<sub>1</sub>, with an EC<sub>50</sub> on k<sub>-1</sub> of 260 μM. However, the changes in the two rates were equal, therefore not altering the net value of K(D) for [<sup>3</sup>H]diazepam binding. Thus phenobarbital acts at the same receptor sites as pentobarbital in this in vitro system, but in a somewhat different manner. These results suggest that barbiturates can be divided into different groups depending on the type of interaction with benzodiazepine receptor binding. The qualitatively different types of interaction with [<sup>3</sup>H]diazepam binding in vitro suggest that the categories so defined might correspond to different categories of pharmacological actions of barbiturates as anesthetics, hypnotics, convulsants, anticonvulsants, or inactive. Testing this theory will require more quantitative information.</p>}},
author = {{Leeb-Lundberg, F. and Olsen, R. W.}},
issn = {{0026-895X}},
language = {{eng}},
month = {{01}},
number = {{2}},
pages = {{320--328}},
publisher = {{American Society for Pharmacology and Experimental Therapeutics}},
series = {{Molecular Pharmacology}},
title = {{Interaction of barbiturates of various pharmacological categories with benzodiazepine receptors}},
url = {{http://molpharm.aspetjournals.org/content/21/2/320}},
volume = {{21}},
year = {{1982}},
}