Commonly Used Therapeutics Associated with Changes in Arousal Inhibit GABA(A)R Activation

• Type of Material: Article
• Authors: Anling Kaplan, Emory University; Abigail I Nash, Janssen Scientific Affairs LLC; Amanda Freeman, Emory University; Lauren G Lewicki, University of Saint Joseph; David Rye, Emory University; Lynn Trotti, Emory University; Asher L Brandt, University of Saint Joseph; Andrew Jenkins, Emory University
• Language: English
• Date: 2023-02-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2023 by the authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/biom13020365
• Title of Journal or Parent Work: BIOMOLECULES
• Volume: 13
• Issue: 2
• Grant/Funding Information: Research reported in this publication was supported by the National Institutes of Neurological Disorders and Stroke of the National Institutes of Health under award number R01NS111280. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
• Keywords: CEREBROSPINAL-FLUID; A RECEPTOR; Science & Technology; OFLOXACIN; KINETICS; GABA(A) receptor; GABA(A)R; arousal; sleep; Life Sciences & Biomedicine; negative allosteric modulator; SLEEP; gamma-aminobutyric acid; DOWN-SYNDROME; FLUMAZENIL; GABA; CLARITHROMYCIN; BRAIN; idiopathic hypersomnia; Biochemistry & Molecular Biology; MODULATION
• Research Categories: Health Sciences, Pharmacy; Chemistry, General

Abstract

GABAA receptor-positive modulators are well-known to induce sedation, sleep, and general anesthesia. Conversely, GABAA receptor negative allosteric modulators (GABAARNAMs) can increase arousal and induce seizures. Motivated by our studies with patients with hypersomnia, and our discovery that two GABAARNAMs can restore the Excitation/Inhibition (E/I) balance in vitro and arousal in vivo, we chose to screen 11 compounds that have been reported to modulate arousal, to see if they shared a GABA-related mechanism. We determined modulation with both conventional and microfluidic patch clamp methods. We found that receptor activation was variably modulated by all 11 compounds: Rifampicin (RIF), Metronidazole (MET), Minocycline (MIN), Erythromycin (ERY), Ofloxacin (OFX), Chloroquine (CQ), Hydroxychloroquine sulfate (HCQ), Flumazenil (FLZ), Pentylenetetrazol (PTZ), (-)-Epigallocatechin Gallate (EGCG), and clarithromycin (CLR). The computational modeling of modulator–receptor interactions predicted drug action at canonical binding sites and novel orphan sites on the receptor. Our findings suggest that multiple avenues of investigation are now open to investigate large and brain-penetrant molecules for the treatment of patients with diminished CNS E/I balance.