Novel positive allosteric modulators of GABAA receptors with anesthetic activity.

Maldifassi, Maria Constanza; Baur, Roland; Pierce, David; Nourmahnad, Anahita; Forman, Stuart A; Sigel, Erwin (2016). Novel positive allosteric modulators of GABAA receptors with anesthetic activity. Scientific Reports, 6(25943), p. 25943. Nature Publishing Group 10.1038/srep25943

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GABAA receptors are the main inhibitory neurotransmitter receptors in the brain and are targets for numerous clinically important drugs such as benzodiazepines, anxiolytics and anesthetics. We previously identified novel ligands of the classical benzodiazepine binding pocket in α1β2γ2 GABAA receptors using an experiment-guided virtual screening (EGVS) method. This screen also identified novel ligands for intramembrane low affinity diazepam site(s). In the current study we have further characterized compounds 31 and 132 identified with EGVS as well as 4-O-methylhonokiol. We investigated the site of action of these compounds in α1β2γ2 GABAA receptors expressed in Xenopus laevis oocytes using voltage-clamp electrophysiology combined with a benzodiazepine site antagonist and transmembrane domain mutations. All three compounds act mainly through the two β+/α- subunit transmembrane interfaces of the GABAA receptors. We then used concatenated receptors to dissect the involvement of individual β+/α- interfaces. We further demonstrated that these compounds have anesthetic activity in a small aquatic animal model, Xenopus laevis tadpoles. The newly identified compounds may serve as scaffolds for the development of novel anesthetics.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

UniBE Contributor:

Maldifassi, Maria Constanza; Baur, Roland and Sigel, Erwin

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

2045-2322

Publisher:

Nature Publishing Group

Language:

English

Submitter:

Barbara Järmann-Bangerter

Date Deposited:

02 Feb 2017 16:28

Last Modified:

11 Sep 2017 14:15

Publisher DOI:

10.1038/srep25943

PubMed ID:

27198062

BORIS DOI:

10.7892/boris.94119

URI:

https://boris.unibe.ch/id/eprint/94119

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