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@ARTICLE{Maleeva:1031972,
author = {Maleeva, Galyna and Nin-Hill, Alba and Wirth, Ulrike and
Rustler, Karin and Ranucci, Matteo and Opar, Ekin and
Rovira, Carme and Bregestovski, Piotr and Zeilhofer, Hanns
Ulrich and König, Burkhard and Alfonso-Prieto, Mercedes and
Gorostiza, Pau},
title = {{L}ight-{A}ctivated {A}gonist-{P}otentiator of {GABA} {A}
{R}eceptors for {R}eversible {N}euroinhibition in {W}ildtype
{M}ice},
journal = {Journal of the American Chemical Society},
volume = {146},
number = {42},
issn = {0002-7863},
address = {Washington, DC},
publisher = {ACS Publications},
reportid = {FZJ-2024-05896},
pages = {28822-28831},
year = {2024},
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.},
cin = {INM-9 / IAS-5},
ddc = {540},
cid = {I:(DE-Juel1)INM-9-20140121 / I:(DE-Juel1)IAS-5-20120330},
pnm = {5241 - Molecular Information Processing in Cellular Systems
(POF4-524) / 5251 - Multilevel Brain Organization and
Variability (POF4-525) / 5252 - Brain Dysfunction and
Plasticity (POF4-525) / DFG project G:(GEPRIS)291198853 -
FOR 2518: Funktionale Dynamik von Ionenkanälen und
Transportern - DynIon - (291198853) / DFG project
G:(GEPRIS)329460521 - Protonentransfer und Substraterkennung
in SLC17-Transportern (329460521)},
pid = {G:(DE-HGF)POF4-5241 / G:(DE-HGF)POF4-5251 /
G:(DE-HGF)POF4-5252 / G:(GEPRIS)291198853 /
G:(GEPRIS)329460521},
typ = {PUB:(DE-HGF)16},
pubmed = {39383450},
UT = {WOS:001335501100001},
doi = {10.1021/jacs.4c08446},
url = {https://juser.fz-juelich.de/record/1031972},
}