Barbituric Acid Derivatives

Gallagher, Brian B.; Freer, L. S.

doi:10.1007/978-3-642-69518-6_14

Cited by 6 publications

(3 citation statements)

References 65 publications

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“…Because the hypnotic properties of barbiturates are related to lipid solubility (reviewed in Gallagher & Freer, 1985), binding sites for anaesthetics may be located in a lipophilic pocket of the receptor, and the transmembrane domains may possibly contain residues that bind pentobarbital. However, in the nicotinic acetylcholine receptor, these regions contain residues which can dramatically affect gating mechanisms, as well (reviewed in Karlin & Akabas, 1995).…”

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confidence: 99%

Structural domains of the human GABA_A receptor β3 subunit involved in the actions of pentobarbital

Serafini

Bracamontes

Steinbach

2000

The Journal of Physiology

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This study was conducted to search for the residues of the β3 subunit which affect pentobarbital action on the γ‐aminobutyric acid type A (GABAA) receptor. Three chimeras were constructed by joining the GABAA receptor β3 subunit to the ρ1 subunit. For each chimera, the N‐terminal sequence was derived from the β3 subunit and the C‐terminal sequence from the ρ1 subunit, with junctions located between the membrane‐spanning regions M2 and M3, in the middle of M2, or in M1, respectively. In receptors obtained by the coexpression of α1 with the chimeric subunits, in contrast with those obtained by the coexpression of α1 and β3, pentobarbital exhibited lower potentiation of GABA‐evoked responses, and in the direct gating of Cl− currents, an increase in the EC50 together with a marked decrease in the relative maximal efficacy compared with that of GABA. Estimates of the channel opening probability through variance analysis and single‐channel recordings of one chimeric subunit showed that the reduced relative efficacy for gating largely resulted from an increase in gating by GABA, with little change in efficacy of pentobarbital. A fit of the time course of the response by the predictions of a class of reaction schemes is consistent with the conclusion that the change in the concentration dependence of activation by pentobarbital is due to a change in pentobarbital affinity for the receptor. Therefore, the data suggest that residues of the β3 subunit involved in pentobarbital binding to GABAA receptors are located downstream from the middle of the M2 region.

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confidence: 99%

Structural domains of the human GABA_A receptor β3 subunit involved in the actions of pentobarbital

Serafini

Bracamontes

Steinbach

2000

The Journal of Physiology

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“…No previous systematic studies have dealt with the effect of anticonvulsant drugs on 3SS-TBPS binding. According to this study, phenobarbital was the only drug that significantly affected 35S-TBPS binding after chronic administration of the drug at the dose known to protect rats from seizures (Gallagher & Freer 1985). Phenobarbital decreased the number of receptor sites in cortical membranes.…”

Section: Discussionmentioning

confidence: 78%

“…The drug doses used in the ex vivo experiment were selected according to the previous data, where such doses were shown to protect rats from several types of seizures (Gallagher & Freer 1985;Jones & Wimbish 1985;Teschendorf & Kretzschmar 1985;Caccia & Garattini 1985). Following daily administration the levels of drugs in rat plasma were found to be of the same magnitude as the known therapeutic concentrations of anticonvulsants in human plasma (Tokola & Neuvonen 1983).…”

Section: Discussionmentioning

confidence: 99%

Effect of Anticonvulsant Drugs on (³⁵S)t‐Butylbicyclophosphorothionate Binding in Vitro and ex Vivo

Pitkänen

Saano

Tuomisto

et al. 1987

Pharmacology & Toxicology

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Using several concentrations of eight anticonvulsant drugs in clinical use (carbamazepine, clonazepam, phenytoin, phenobarbital, ethosuximide, primidone, sodium valproate, and D,L-gamma-vinyl GABA), we studied their abilities in vitro to displace (35S)t-butylbicyclophosphorothionate (35S-TBPS) from its binding site in a homogenate of rat brain. Thereafter ethosuximide (150 mg/kg), phenobarbital (30 mg/kg), clonazepam (0.3 mg/kg), or phenytoin (100 mg/kg) was injected intraperitoneally into rats for 16-20 days; and the effect of drug administration on 35S-TBPS binding was studied in the cortex and hippocampus ex vivo. Phenobarbital (100 microM, P less than 0.001), ethosuximide (500 microM, P less than 0.001), and phenytoin (40 microM, P less than 0.001) decreased the specific 35S-TBPS binding in vitro by 10-16%. After drug administration of phenobarbital (concentration in plasma 168 microM), the number of binding sites decreased and the binding affinity (P less than 0.05) in the cortex increased. Other anticonvulsants did not modulate 35S-TBPS binding in vitro at the concentration analogous to therapeutic plasma levels or ex vivo at the dose used. These results suggest that the use of phenobarbital may modulate the TBPS binding site, but the role of the present findings in the anticonvulsant action of phenobarbital needs to be further studied.

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Older Anticonvulsants Continuing in Use but with Limited Advance in Knowledge

Eadie¹,

Vajda²

1999

Antiepileptic Drugs

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Barbituric Acid Derivatives

Cited by 6 publications

References 65 publications

Structural domains of the human GABA_A receptor β3 subunit involved in the actions of pentobarbital

Structural domains of the human GABA_A receptor β3 subunit involved in the actions of pentobarbital

Effect of Anticonvulsant Drugs on (³⁵S)t‐Butylbicyclophosphorothionate Binding in Vitro and ex Vivo

Older Anticonvulsants Continuing in Use but with Limited Advance in Knowledge

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Barbituric Acid Derivatives

Cited by 6 publications

References 65 publications

Structural domains of the human GABAA receptor β3 subunit involved in the actions of pentobarbital

Structural domains of the human GABAA receptor β3 subunit involved in the actions of pentobarbital

Effect of Anticonvulsant Drugs on (35S)t‐Butylbicyclophosphorothionate Binding in Vitro and ex Vivo

Older Anticonvulsants Continuing in Use but with Limited Advance in Knowledge

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Product

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Structural domains of the human GABA_A receptor β3 subunit involved in the actions of pentobarbital

Structural domains of the human GABA_A receptor β3 subunit involved in the actions of pentobarbital

Effect of Anticonvulsant Drugs on (³⁵S)t‐Butylbicyclophosphorothionate Binding in Vitro and ex Vivo