How theories evolved concerning the mechanism of action of barbiturates

  title={How theories evolved concerning the mechanism of action of barbiturates},
  author={Wolfgang L{\"o}scher and Michael A. Rogawski},
The barbiturate phenobarbital has been in use in the treatment of epilepsy for 100 years. It has long been recognized that barbiturates act by prolonging and potentiating the action of γ‐aminobutyric acid (GABA) on GABAA receptors and at higher concentrations directly activating the receptors. A large body of data supports the concept that GABAA receptors are the primary central nervous system target for barbiturates, including the finding that transgenic mice with a point mutation in the β3… 
Shared structural mechanisms of general anesthetics and benzodiazepines
Cryo-electron microscopy structures of GABA A receptors bound to intravenous anaesthetic and benzodiazepines reveal both common and distinct transmembrane binding sites, and show that the mechanisms of action of anaesthetics partially overlap with those of benzodiazines.
Contrasting actions of a convulsant barbiturate and its anticonvulsant enantiomer on the α1β3γ2L GABAA receptor account for their in vivo effects
A novel pair of chiral barbiturates are synthesized and characterized that are capable of photolabelling their binding sites on GABAA receptors and, in mice, only the anticonvulsant R‐enantiomer binds to the enhancing site on open channels, causing them to stay open longer.
The Pharmacology of Imepitoin: The First Partial Benzodiazepine Receptor Agonist Developed for the Treatment of Epilepsy
The more favorable pharmacokinetic profile of imepitoin in dogs versus humans led to the decision to develop imePitoin for the treatment of canine epilepsy, and the drug was recently approved for this indication in Europe.
Differential modulation of GABA(A) receptor function by aryl pyrazoles.
Mechanisms of Action of Antiseizure Drugs and the Ketogenic Diet.
The ketogenic diet leads to increases in circulating ketones, which may contribute to the efficacy in treating pharmacoresistant seizures, and is one treatment option for drug-resistant patients.
Phenobarbital is still widely used for neonatal and childhood seizures and for drug-resistant convulsive and nonconvulsive status epilepticus and recent data have confirmed, in a prospective cohort of women taking phenobarbITAL as monotherapy, that the drug can be associated with a range of congenital defects in exposed infants.
Effects of midazolam, pentobarbital and ketamine on the mRNA expression of ion channels in a model organism Daphnia pulex
The mRNA profile changes in this study may reflect the molecular targets not only in drug actions, but also in chronic drug addiction, and suggest the possibility that hypnotic/anesthetic drugs are capable of altering the functions of the nervous system, as well as those non-nerve tissues with abundant ion channel expressions.
Barbiturates Bind in the GLIC Ion Channel Pore and Cause Inhibition by Stabilizing a Closed State*♦
The identification of this pore binding site sheds light on the mechanism of barbiturate inhibition of cationic pLGICs and allows the rationalization of several structural and functional features previously observed for barbiturates.
The ups and downs of alkyl‐carbamates in epilepsy therapy: How does cenobamate differ?
Results from recent randomized controlled clinical trials with cenobamate suggest that this newest antiseizure alkyl‐carbamate possesses a degree of efficacy not witnessed since felbamate was approved in 1993, and it is not clear whether this impressive efficacy reflects an as yet undescribed mechanism of action or whether it possesses a unique synergy between its actions at the GABAA receptor and on persistent Na+ currents.


Identification of a Molecular Target Mediating the General Anesthetic Actions of Pentobarbital
A clear pharmacological dissociation of the immobilizing/hypnotic and respiratory/cardiovascular actions of pentobarbital is shown.
Identification of Structures within GABAA Receptor α Subunits That Regulate the Agonist Action of Pentobarbital
This work has identified a structural difference in GABAR α subtypes that regulates direct activation by barbiturates and indicates that only one mutation, α6(T69K), altered pentobarbital efficacy.
Barbiturate receptor sites are coupled to benzodiazepine receptors.
The results suggest that picrotoxin-sensitive barbiturate binding sites are coupled to benzodiazepine receptors in the gamma-aminobutyric acid receptor-ionophore complex, and that these binding sites have the properties of pharmacologically relevant receptors that mediate at least part of the action of various nervous system depressant and excitatory drugs.
Barbiturate interactions at the human GABAA receptor: dependence on receptor subunit combination
The results indicate that GABAA receptors containing α6 subunits have both a higher affinity and efficacy for direct activation by pentobarbitone, and reveal that pentobarbitsone binds to more than one site on the GAB AA receptor, and these are dependent on receptor subunit composition.
Anticonvulsant drug mechanisms of action.
Distinct structural changes in the GABAA receptor elicited by pentobarbital and GABA.
Facilitation of recurrent inhibition in rat hippocampus by barbiturate and related nonbarbiturate depressant drugs.
There was a good correspondence between the potencies of these drugs in facilitating inhibition and their previously reported abilities to regulate binding at the gamma-aminobutyric acid/benzodiazepine/barbiturate receptor complex, and the net effects observed with each drug tested correlated well with the behavioral effects of these agents in vivo.
GABAA receptors as molecular targets of general anesthetics: identification of binding sites provides clues to allosteric modulation
  • R. Olsen, Guodong Li
  • Medicine
    Canadian journal of anaesthesia = Journal canadien d'anesthesie
  • 2011
Establishment of a coherent and consistent structural model of the GABAA-R lends support to the conclusion that general anesthetics can modulate function by binding to appropriate domains on the protein.