Zolpidem and eszopiclone prime alpha1beta2gamma2 GABAA receptors for longer duration of activity.

Article Details


Dixon CL, Harrison NL, Lynch JW, Keramidas A

Zolpidem and eszopiclone prime alpha1beta2gamma2 GABAA receptors for longer duration of activity.

Br J Pharmacol. 2015 Jul;172(14):3522-36. doi: 10.1111/bph.13142. Epub 2015 May 11.

PubMed ID
25817320 [ View in PubMed

BACKGROUND AND PURPOSE: GABAA 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 alpha1beta2gamma2 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 alpha1beta2gamma2 GABAA receptors. Drug binding and modulation was quantified with the aid of an activation mechanism. KEY RESULTS: At the single-channel level, the drugs prolonged the duration of receptor activation, with similar KD values of approximately 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.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
EszopicloneGABA(A) Receptor (Protein Group)Protein groupHumans
Positive allosteric modulator