Light-Activated Agonist-Potentiator of GABA<sub>A</sub> Receptors for Reversible Neuroinhibition in Wildtype Mice

Gamma aminobutyric acid type A receptors (GABA<sub>A</sub>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<sub>A</sub>Rs inevitably causes adverse effects regardless of the drug selectivity. Therefore, therapeutic guidelines must often limit or exclude clinically available GABA<sub>A</sub>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<sub>A</sub>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 <i>in vitro</i> 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 <i>in vivo</i> 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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Publication Details

Journal
Journal of the American Chemical Society
Published
2024-10-09
DOI
https://doi.org/10.1021/jacs.4c08446
Citations
6
Primary Topic
Photochromic and Fluorescence Chemistry
Type
article
Field-Weighted Citation Impact
0.70

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article

Light-Activated Agonist-Potentiator of GABAA Receptors for Reversible Neuroinhibition in Wildtype Mice

Ekin Opar, Karin Rustler, Mercedes Alfonso‐Prieto, Ulrike Wirth et al.
6 citations
Journal of the American Chemical Society
Photochromic and Fluorescence Chemistry
0.70
article

Light-Activated Agonist-Potentiator of GABAA Receptors for Reversible Neuroinhibition in Wildtype Mice

Ekin Opar, Karin Rustler, Mercedes Alfonso‐Prieto, Ulrike Wirth, Galyna Maleeva, Pìotr Bregestovski, Pau Gorostiza, Carme Rovira, Alba Nin‐Hill, Matteo Ranucci, Burkhard König, Hanns Ulrich Zeilhofer
article en
6 citations

Abstract

Gamma aminobutyric acid type A receptors (GABA<sub>A</sub>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<sub>A</sub>Rs inevitably causes adverse effects regardless of the drug selectivity. Therefore, therapeutic guidelines must often limit or exclude clinically available GABA<sub>A</sub>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<sub>A</sub>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 <i>in vitro</i> 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 <i>in vivo</i> 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.

Journal of the American Chemical SocietyVol. 146(42)
Institució Catalana de Recerca i Estudis Avançats (ES), Inserm (FR), Forschungszentrum Jülich (DE), University of Zurich (CH), Aix-Marseille Université (FR), Instituto de Salud Carlos III (ES), ETH Zurich (CH), Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (ES), Institut de Neurosciences des Systèmes (FR), Barcelona Institute of Science and Technology (ES), Institute for Bioengineering of Catalonia (ES), Instituto de Química Orgánica General (ES), University of Regensburg (DE), Universitat de Barcelona (ES)
Aix-Marseille Université, Ministerio de Ciencia, Innovación y Universidades, Centres de Recerca de Catalunya, European Commission, Deutsche Forschungsgemeinschaft, Institut National de la Santé et de la Recherche Médicale, Generalitat de Catalunya, Institució Catalana de Recerca i Estudis Avançats, Ministerio de Ciencia e Innovación, Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina, Universität Regensburg, Universitat de Barcelona, Universität Zürich, Institute for Bioengineering of Catalonia, Horizon 2020 Framework Programme, Agència de Gestió d'Ajuts Universitaris i de Recerca, Instituto de Salud Carlos III, European Regional Development Fund, Agencia Estatal de Investigación, H2020 Future and Emerging Technologies, HORIZON EUROPE European Innovation Council, H2020 LEIT Information and Communication Technologies
Zero hunger
Openalex Percentile: Top 29%
Photochromic and Fluorescence Chemistry
0.70
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