ArticleBritish journal of pharmacology2015
Zolpidem and eszopiclone prime α1β2γ2 GABAA receptors for longer duration of activity.
Article in British journal of pharmacology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers, 1 of them a synthesis that pooled it.
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Who cites it
19 citing papers in PubMed, 1 synthesis or guideline pooled it, 31 citations in OpenAlex.
- Sleep and the Pharmacotherapy of Alcohol Use Disorder: Unfortunate Bedfellows. A Systematic Review With Meta-Analysis.Frontiers in pharmacology · 2019Pooled it
- Recommendations on Switching or Deprescribing Hypnotic Medications for Insomnia.Deutsches Arzteblatt international · 2026Review
- Suicide adverse events associated with zopiclone and eszopiclone: A pharmacovigilance analysis based on FAERS, JADER and CVARD.PloS one · 2026Article
- Microglial TNFα controls daily changes in synaptic GABAARs and sleep slow waves.The Journal of cell biology · 2024Article
- Terpenoids derived fromHeliyon · 2024Article
- Anti-seizure mechanisms of midazolam and valproate at the β2(L51M) variant of the GABANeuropharmacology · 2022Article
- Benzodiazepine Modulation of GABABiomolecules · 2022Review
- The assessment of risk factors for postoperative delirium using cubic spline curves in gastroenterological surgery.Surgery today · 2021Article
- Susceptibility to chronic immobilization stress-induced depressive-like behaviour in middle-aged female mice and accompanying changes in dopamine D1 and GABABehavioral and brain functions : BBF · 2021Article
- Mechanisms Underlying the Action of Ziziphi Spinosae Semen in the Treatment of Insomnia: A Study Involving Network Pharmacology and Experimental Validation.Frontiers in pharmacology · 2021Article
- Eszopiclone and Zolpidem Produce Opposite Effects on Hippocampal Ripple Density.Frontiers in pharmacology · 2021Article
- GABAFrontiers in cellular neuroscience · 2020Article
- The dual-gate model for pentameric ligand-gated ion channels activation and desensitization.The Journal of physiology · 2018Review
- Distinct Modulation of Spontaneous and GABA-Evoked Gating by Flurazepam Shapes Cross-Talk Between Agonist-Free and Liganded GABAFrontiers in cellular neuroscience · 2018Article
- Common Ribs of Inhibitory Synaptic Dysfunction in the Umbrella of Neurodevelopmental Disorders.Frontiers in molecular neuroscience · 2018Review
- SAHA (Vorinostat) Corrects Inhibitory Synaptic Deficits Caused by Missense Epilepsy Mutations to the GABAFrontiers in molecular neuroscience · 2018Article
- Investigating the Mechanism by Which Gain-of-function Mutations to the α1 Glycine Receptor Cause Hyperekplexia.The Journal of biological chemistry · 2016Article
- Insomnia in the Military: Application and Effectiveness of Cognitive and Pharmacologic Therapies.Current psychiatry reports · 2015Review
- Generation of Functional Inhibitory Synapses Incorporating Defined Combinations of GABA(A) or Glycine Receptor Subunits.Frontiers in molecular neuroscience · 2015Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
background and purposeGABAA receptors mediate neuronal inhibition in the brain. They are the primary targets for benzodiazepines, which are widely used to treat neurological disorders including anxiety, epilepsy and insomnia. The mechanism by which benzodiazepines enhance GABAA receptor activity has been extensively studied, but there is little mechanistic information on how non-benzodiazepine drugs that bind to the same site exert their effects. Eszopiclone and zolpidem are two non-benzodiazepine drugs for which no mechanism of action has yet been proposed, despite their clinical importance as sleeping aids. Here we investigate how both drugs enhance the activity of α1β2γ2 GABAA receptors. EXPERIMENTAL APPROACH: We used rapid ligand application onto macropatches and single-channel kinetic analysis to assess rates of current deactivation. We also studied synaptic currents in primary neuronal cultures and in heterosynapses, whereby native GABAergic nerve terminals form synapses with HEK293 cells expressing α1β2γ2 GABAA receptors. Drug binding and modulation was quantified with the aid of an activation mechanism. KEY
resultsAt the single-channel level, the drugs prolonged the duration of receptor activation, with similar KD values of ∼80 nM. Channel activation was prolonged primarily by increasing the equilibrium constant between two connected shut states that precede channel opening. CONCLUSIONS AND IMPLICATIONS: As the derived mechanism successfully simulated the effects of eszopiclone and zolpidem on ensemble currents, we propose it as the definitive mechanism accounting for the effects of both drugs. Importantly, eszopiclone and zolpidem enhanced GABAA receptor currents via a mechanism that differs from that proposed for benzodiazepines.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.