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Light-Activated Agonist-Potentiator of GABA$_{A}$ Receptors for Reversible Neuroinhibition in Wildtype Mice

Maleeva, Galyna; Nin-Hill, Alba; Wirth, Ulrike; Rustler, Karin; Ranucci, Matteo; Opar, Ekin; Rovira, Carme; Bregestovski, Piotr; Zeilhofer, Hanns Ulrich; König, Burkhard; Alfonso-Prieto, Mercedes; Gorostiza, Pau (2024). Light-Activated Agonist-Potentiator of GABA$_{A}$ Receptors for Reversible Neuroinhibition in Wildtype Mice. Journal of the American Chemical Society, 146(42):28822-28831.

Abstract

Gamma aminobutyric acid type A receptors (GABA$_{A}$Rs) play a key role in the mammalian central nervous system (CNS) as drivers of neuroinhibitory circuits, which are commonly targeted for therapeutic purposes with potentiator drugs. However, due to their widespread expression and strong inhibitory action, systemic pharmaceutical potentiation of GABA$_{A}$Rs inevitably causes adverse effects regardless of the drug selectivity. Therefore, therapeutic guidelines must often limit or exclude clinically available GABA$_{A}$R potentiators, despite their high efficacy, good biodistribution, and favorable molecular properties. One solution to this problem is to use drugs with light-dependent activity (photopharmacology) in combination with on-demand, localized illumination. However, a suitable light-activated potentiator of GABA$_{A}$Rs has been elusive so far for use in wildtype mammals. We have met this need by developing azocarnil, a diffusible GABAergic agonist-potentiator based on the anxiolytic drug abecarnil that is inactive in the dark and activated by visible violet light. Azocarnil can be rapidly deactivated with green light and by thermal relaxation in the dark. We demonstrate that it selectively inhibits neuronal currents in hippocampal neurons in vitro and in the dorsal horns of the spinal cord of mice, decreasing the mechanical sensitivity as a function of illumination without displaying systemic adverse effects. Azocarnil expands the in vivo photopharmacological toolkit with a novel chemical scaffold and achieves a milestone toward future phototherapeutic applications to safely treat muscle spasms, pain, anxiety, sleep disorders, and epilepsy.

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Pharmacology and Toxicology
07 Faculty of Science > Institute of Pharmacology and Toxicology
Dewey Decimal Classification:610 Medicine & health
570 Life sciences; biology
Scopus Subject Areas:Physical Sciences > Catalysis
Physical Sciences > General Chemistry
Life Sciences > Biochemistry
Physical Sciences > Colloid and Surface Chemistry
Language:English
Date:23 October 2024
Deposited On:26 Nov 2024 08:24
Last Modified:31 Jan 2025 02:39
Publisher:American Chemical Society (ACS)
ISSN:0002-7863
OA Status:Hybrid
Publisher DOI:https://doi.org/10.1021/jacs.4c08446
PubMed ID:39383450
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  • Language: English
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