Commonly Used Therapeutics Associated with Changes in Arousal Inhibit GABA<sub<A</sub<R Activation

GABA<sub<A</sub< receptor-positive modulators are well-known to induce sedation, sleep, and general anesthesia. Conversely, GABA<sub<A</sub< receptor negative allosteric modulators (GABA<sub<A</sub<RNAMs) can increase arousal and induce seizures. Motivated by our...
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Gespeichert in:

Autor*in:	Anling Kaplan [verfasserIn] Abigail I. Nash [verfasserIn] Amanda A. H. Freeman [verfasserIn] Lauren G. Lewicki [verfasserIn] David B. Rye [verfasserIn] Lynn Marie Trotti [verfasserIn] Asher L. Brandt [verfasserIn] Andrew Jenkins [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2023

Schlagwörter:	gamma-aminobutyric acid GABA GABA GABA negative allosteric modulator arousal

Übergeordnetes Werk:	In: Biomolecules - MDPI AG, 2013, 13(2023), 2, p 365
Übergeordnetes Werk:	volume:13 ; year:2023 ; number:2, p 365

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3390/biom13020365

Katalog-ID:	DOAJ080999735

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author	Anling Kaplan
spellingShingle	Anling Kaplan misc QR1-502 misc gamma-aminobutyric acid misc GABA misc GABA<sub<A</sub< receptor misc GABA<sub<A</sub<R misc negative allosteric modulator misc arousal misc Microbiology Commonly Used Therapeutics Associated with Changes in Arousal Inhibit GABA<sub<A</sub<R Activation
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topic_title	QR1-502 Commonly Used Therapeutics Associated with Changes in Arousal Inhibit GABA<sub<A</sub<R Activation gamma-aminobutyric acid GABA GABA<sub<A</sub< receptor GABA<sub<A</sub<R negative allosteric modulator arousal
topic	misc QR1-502 misc gamma-aminobutyric acid misc GABA misc GABA<sub<A</sub< receptor misc GABA<sub<A</sub<R misc negative allosteric modulator misc arousal misc Microbiology
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title	Commonly Used Therapeutics Associated with Changes in Arousal Inhibit GABA<sub<A</sub<R Activation
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title_full	Commonly Used Therapeutics Associated with Changes in Arousal Inhibit GABA<sub<A</sub<R Activation
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title_sort	commonly used therapeutics associated with changes in arousal inhibit gaba<sub<a</sub<r activation
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title_auth	Commonly Used Therapeutics Associated with Changes in Arousal Inhibit GABA<sub<A</sub<R Activation
abstract	GABA<sub<A</sub< receptor-positive modulators are well-known to induce sedation, sleep, and general anesthesia. Conversely, GABA<sub<A</sub< receptor negative allosteric modulators (GABA<sub<A</sub<RNAMs) can increase arousal and induce seizures. Motivated by our studies with patients with hypersomnia, and our discovery that two GABA<sub<A</sub<RNAMs 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.
abstractGer	GABA<sub<A</sub< receptor-positive modulators are well-known to induce sedation, sleep, and general anesthesia. Conversely, GABA<sub<A</sub< receptor negative allosteric modulators (GABA<sub<A</sub<RNAMs) can increase arousal and induce seizures. Motivated by our studies with patients with hypersomnia, and our discovery that two GABA<sub<A</sub<RNAMs 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.
abstract_unstemmed	GABA<sub<A</sub< receptor-positive modulators are well-known to induce sedation, sleep, and general anesthesia. Conversely, GABA<sub<A</sub< receptor negative allosteric modulators (GABA<sub<A</sub<RNAMs) can increase arousal and induce seizures. Motivated by our studies with patients with hypersomnia, and our discovery that two GABA<sub<A</sub<RNAMs 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.
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title_short	Commonly Used Therapeutics Associated with Changes in Arousal Inhibit GABA<sub<A</sub<R Activation
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