Light-Activated Agonist-Potentiator of GABAA Receptors for Reversible Neuroinhibition in Wildtype Mice
Year: 2024
Type: article
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.
Authors: Maleeva, Galyna, Nin-Hill, Alba, Wirth, Ulrike, Rustler, Karin, Ranucci, Matteo, Opar, Ekin, Rovira, Carme, Bregestovski, Piotr, Zeilhofer, Hanns U., König, Burkhard, Alfonso-Prieto, Mercedes, Gorostiza, Pau
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Funders: 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, Agencia Estatal de Investigación, HORIZON EUROPE European Innovation Council
Awards: G121809054, G145641598, G1510469474, G1694977573, G1855990336, G206750343, G2262748287, G2304947563, G2543706835, G2576988154, G2660406951, G2907678734, G2979234808, G3005324705, G3480869486, G3547363112, G3681454997, G3690828678, G3742369756, G3936970252, G4042783231, G425668148, G434337789, G4863353618, G5175525644, G5285093374, G5421974903, G5477392707, G5520398682, G5555131222, G556856207, G5805502524, G5852091828, G5932392626, G6148272825, G657093227, G6602917831, G6656126374, G6731524417, DEEP BRAIN PHOTONIC TOOLS FOR CELL-TYPE SPECIFIC TARGETING OF NEURAL DISEASES, G7084143925, G734693063, G7425137858, G7863371703, G811525415, G8347645112, G8373511800, G8434830731, G8447332696, G8447737365, G8497050386, G8684520763, Human Brain Project Specific Grant Agreement 3
OpenAlex ID: W6891504267
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