Light-Activated Agonist-Potentiator\nof GABA<sub>A</sub> Receptors for Reversible Neuroinhibition in Wildtype\nMice

Gamma aminobutyric acid type A receptors (GABA<sub>A</sub>Rs) play\na key role in the mammalian central nervous system (CNS) as drivers\nof neuroinhibitory circuits, which are commonly targeted for therapeutic\npurposes with potentiator drugs. However, due to their widespread\nexpression and strong inhibitory action, systemic pharmaceutical potentiation\nof GABA<sub>A</sub>Rs inevitably causes adverse effects regardless\nof the drug selectivity. Therefore, therapeutic guidelines must often\nlimit or exclude clinically available GABA<sub>A</sub>R potentiators,\ndespite their high efficacy, good biodistribution, and favorable molecular\nproperties. One solution to this problem is to use drugs with light-dependent\nactivity (photopharmacology) in combination with on-demand, localized\nillumination. However, a suitable light-activated potentiator of GABA<sub>A</sub>Rs has been elusive so far for use in wildtype mammals. We\nhave met this need by developing azocarnil, a diffusible GABAergic\nagonist-potentiator based on the anxiolytic drug abecarnil that is\ninactive in the dark and activated by visible violet light. Azocarnil\ncan be rapidly deactivated with green light and by thermal relaxation\nin the dark. We demonstrate that it selectively inhibits neuronal\ncurrents in hippocampal neurons <i>in vitro</i> and in the\ndorsal horns of the spinal cord of mice, decreasing the mechanical\nsensitivity as a function of illumination without displaying systemic\nadverse effects. Azocarnil expands the <i>in vivo</i> photopharmacological\ntoolkit with a novel chemical scaffold and achieves a milestone toward\nfuture phototherapeutic applications to safely treat muscle spasms,\npain, anxiety, sleep disorders, and epilepsy.