• Megan McGrath, Mansi Tolia, and Douglas E Raines.
• Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, 55 Fruit Street, GRB444, Boston, MA, 02114, USA.
• Pharmacol Rep. 2020 Feb 1; 72 (1): 260-266.

BackgroundMany sedative-hypnotic agents are thought to act by positively modulating γ-aminobutyric acid type A (GABAA) receptors. However, for many agents, the location(s) of the binding site(s) responsible for such receptor modulation is uncertain. We previously developed a low efficacy ligand (naphthalene-etomidate) that binds within a homologous set of hydrophobic cavities located at GABAA receptor subunit interfaces in the transmembrane domain, and thus acts as a competitive antagonist for higher efficacy sedative-hypnotics that also bind to these sites. In this report, we describe studies using this compound as a pharmacological screening tool to test whether sedative-hypnotics representing a range of chemical classes can modulate GABAA receptors by binding within these receptor cavities.MethodsThe impact of naphthalene-etomidate on GABA-evoked currents that were mediated by oocyte-expressed α1β3γ2L GABAA receptors and potentiated by muscimol, alphaxalone, 2,2,2-trichloroethanol, isoflurane, AA29504, loreclezole, or diazepam was quantified using electrophysiological techniques.ResultsNaphthalene-etomidate (300 µM) significantly reduced GABAA receptor currents potentiated by alphaxalone (by 22 ± 11%), 2,2,2-trichloroethanol (by 23 ± 6%), isoflurane (by 32 ± 10%), AA29504 (by 41 ± 6%), loreclezole (by 43 ± 9%), but significantly increased those potentiated by muscimol (by 26 ± 11%). Naphthalene-etomidate significantly increased currents potentiated by a low (1 µM) diazepam concentration (by 56 ± 14%) while reducing those potentiated by a high (100 µM) diazepam concentration (by 11 ± 7%).ConclusionsOur results suggest that many (but not all) sedative-hypnotics are capable of positively modulating the GABAA receptor by binding within a common set of hydrophobic cavities.

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