TY  - JOUR
AU  - Maleeva, Galyna
AU  - Nin-Hill, Alba
AU  - Wirth, Ulrike
AU  - Rustler, Karin
AU  - Ranucci, Matteo
AU  - Opar, Ekin
AU  - Rovira, Carme
AU  - Bregestovski, Piotr
AU  - Zeilhofer, Hanns Ulrich
AU  - König, Burkhard
AU  - Alfonso-Prieto, Mercedes
AU  - Gorostiza, Pau
TI  - Light-Activated Agonist-Potentiator of GABA A Receptors for Reversible Neuroinhibition in Wildtype Mice
JO  - Journal of the American Chemical Society
VL  - 146
IS  - 42
SN  - 0002-7863
CY  - Washington, DC
PB  - ACS Publications
M1  - FZJ-2024-05896
SP  - 28822-28831
PY  - 2024
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - 39383450
UR  - <Go to ISI:>//WOS:001335501100001
DO  - DOI:10.1021/jacs.4c08446
UR  - https://juser.fz-juelich.de/record/1031972
ER  -