Journal Article

FZJ-2024-05896

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Light-Activated Agonist-Potentiator of GABA A Receptors for Reversible Neuroinhibition in Wildtype Mice

Maleeva, G. ; Nin-Hill, A. ; Wirth, U. ; Rustler, K. ; Ranucci, M. ; Opar, E. ; Rovira, C. ; Bregestovski, P. ; Zeilhofer, H. U. ; König, B. ; Alfonso-Prieto, M. (Corresponding author)FZJ* ; Gorostiza, P. (Corresponding author)

2024
ACS Publications Washington, DC

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Please use a persistent id in citations: doi:10.1021/jacs.4c08446  doi:10.34734/FZJ-2024-05896

Abstract: Gamma aminobutyric acid type A receptors (GABAARs) 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 GABAARs inevitably causes adverse effects regardless of the drug selectivity. Therefore, therapeutic guidelines must often limit or exclude clinically available GABAAR 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 GABAARs 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.

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Contributing Institute(s):

1. Computational Biomedicine (INM-9)
2. Computational Biomedicine (IAS-5)

Research Program(s):

1. 5241 - Molecular Information Processing in Cellular Systems (POF4-524) (POF4-524)
2. 5251 - Multilevel Brain Organization and Variability (POF4-525) (POF4-525)
3. 5252 - Brain Dysfunction and Plasticity (POF4-525) (POF4-525)
4. DFG project G:(GEPRIS)291198853 - FOR 2518: Funktionale Dynamik von Ionenkanälen und Transportern - DynIon - (291198853) (291198853)
5. DFG project G:(GEPRIS)329460521 - Protonentransfer und Substraterkennung in SLC17-Transportern (329460521) (329460521)

Appears in the scientific report 2024

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