2. Academic Validation
  3. Light-Activated Agonist-Potentiator of GABAA Receptors for Reversible Neuroinhibition in Wildtype Mice

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

  • J Am Chem Soc. 2024 Oct 23;146(42):28822-28831. doi: 10.1021/jacs.4c08446.
Galyna Maleeva 1 2,  Alba Nin-Hill 3,  Ulrike Wirth 4,  Karin Rustler 4,  Matteo Ranucci 5,  Ekin Opar 1 2 6,  Carme Rovira 3 7,  Piotr Bregestovski 8,  Hanns Ulrich Zeilhofer 5 9,  Burkhard König 4,  Mercedes Alfonso-Prieto 10,  Pau Gorostiza 1 2 7
Affiliations

Affiliations

  • 1 Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute for Science and Technology, Barcelona 08028, Spain.
  • 2 Networking Biomedical Center in Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), ISCIII, Barcelona 08028, Spain.
  • 3 Departament de Química Inorgànica i Orgànica (Secció de Química Orgànica) & Institut de Química Teòrica i Computacional (IQTCUB), Universitat de Barcelona, Barcelona 08020, Spain.
  • 4 Institute of Organic Chemistry, University of Regensburg, Regensburg 93053, Germany.
  • 5 Institute of Pharmacology and Toxicology, University of Zurich, Zürich 8057, Switzerland.
  • 6 Doctorate program of the University of Barcelona, Barcelona 08020, Spain.
  • 7 Catalan Institution for Research and Advanced Studies (ICREA), Barcelona 08010, Spain.
  • 8 Institut de Neurosciences des Systèmes, UMR INSERM 1106, Aix-Marseille Université, Marseille 13005, France.
  • 9 Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Zürich, Zürich 8093, Switzerland.
  • 10 Institute of Neuroscience and Medicine INM-9 Computational Biomedicine, Forschungszentrum Jülich GmbH, D-52428 Jülich, Germany.
PMID: 39383450 DOI: 10.1021/jacs.4c08446
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.

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