Development of a quaternary ammonium photoswitchable antagonist of NMDA receptors

NMDA receptors play critical roles in numerous physiological and pathological processes in CNS that requires development of modulating ligands. In particular, photoswitchable compounds that selectively target NMDA receptors would be particularly useful for analysis of receptor contributions to vario...

Full description

Saved in:
Bibliographic Details
Published in:European journal of pharmacology 2023-01, Vol.938, p.175448-175448, Article 175448
Main Authors: Nikolaev, Maxim V., Strashkov, Daniil M., Ryazantsev, Mikhail N., Tikhonov, Denis B.
Format: Article
Language:English
Subjects:
Ammonium Compounds - pharmacology
Animals
Azo Compounds - chemistry
Azo Compounds - pharmacology
Inhibition
NMDA receptor
Photopharmacology
Photoswitches
Rats
Receptors, Glutamate
Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:NMDA receptors play critical roles in numerous physiological and pathological processes in CNS that requires development of modulating ligands. In particular, photoswitchable compounds that selectively target NMDA receptors would be particularly useful for analysis of receptor contributions to various processes. Recently, we identified a light-dependent anti-NMDA activity of the azobenzene-containing quaternary ammonium compounds DENAQ (diethylamine-azobenzene-quaternary ammonium) and DMNAQ (dimethylamine-azobenzene-quaternary ammonium). Here, we developed a series of light-sensitive compounds based on the DENAQ structure, and studied their action on glutamate receptors in rat brain neurons using patch-clamp method. We found that the activities of the compounds and the influence of illumination strongly depended on the structural details, as even minor structural modifications greatly altered the activity and sensitivity to illumination. The compound PyrAQ (pyrrolidine-azobenzene-quaternary ammonium) was the most active and produced fast and fully reversible inhibition of NMDA receptors. The IC50 values under ambient and monochromic light conditions were 2 and 14 μM, respectively. The anti-AMPA activity was much weaker. The action of PyrAQ did not depend on NMDA receptor activity, agonist concentration, or membrane voltage, making it a useful tool for photopharmacological studies.
ISSN:0014-2999
1879-0712
DOI:10.1016/j.ejphar.2022.175448