Molecular Actions of (S)-Desmethylzopiclone (SEP-174559), an Anxiolytic Metabolite of Zopiclone

• Published in: The Journal of pharmacology and experimental therapeutics 2002-08, Vol.302 (2), p.612-618
• Main Author: Fleck, Mark W
• Format: Article
• Language: English
• Subjects: Anti-Anxiety Agents - pharmacology; Cell Line; Humans; Hypnotics and Sedatives - pharmacology; Kidney; Membrane Potentials - drug effects; Membrane Potentials - physiology; Nicotinic Antagonists - pharmacology; Piperazines - pharmacology; Receptors, GABA-A - drug effects; Receptors, GABA-A - physiology; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - physiology; Receptors, Nicotinic - drug effects; Receptors, Nicotinic - physiology; Transfection
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.102.033886

This study set out to profile the activity of ( S )-desmethylzopiclone (SEP-174559) at subtypes of the γ-aminobutyric acid type-A (GABA A ) receptor and other neurotransmitter receptor ion channels. Recombinant receptors were expressed in human embryonic kidney 293 cells and examined functionally by patch-clamp recording with fast perfusion of agonist and drug solutions. Micromolar concentrations of SEP-174559 potentiated GABA A receptor currents evoked by subsaturating concentrations of GABA. The potentiation was related to a leftward shift in the GABA dose-response curves, suggesting the drug acts to increase GABA binding affinity. The potentiation strictly required the presence of the γ2 subunit; no enhancement was seen for receptors containing instead the γ1 subunit or lacking a γ subunit altogether. SEP-174559 and its parent compound, racemic zopiclone, were not selective between α1-, α2-, or α3-bearing GABA A receptors. Within the nicotinic receptor superfamily, SEP-174559 did not affect serotonin type-3 receptor function but was found to inhibit nicotinic acetylcholine (nACh) receptors. The inhibition of nACh receptors was noncompetitive and was mimicked by zopiclone, alprazolam, and diazepam. In the glutamate receptor superfamily, SEP-174559 inhibited N -methyl- d -aspartate (NMDA) receptor currents but did not affect non-NMDA receptors. These data confirm that SEP-174559 has benzodiazepine-like actions at γ2-bearing subtypes of the GABA A receptor and suggest additional actions of benzodiazepine-site ligands at nACh and NMDA receptors.