Development of a quaternary ammonium photoswitchable antagonist of NMDA receptors.

Autor: Nikolaev MV; Sechenov Institute of Evolutionary Physiology and Biochemistry of RAS, 194223, Saint Petersburg, Russia. Electronic address: fmedfstud@gmail.com., Strashkov DM; Saint Petersburg National Research Academic University of the Russian Academy of Sciences, 194021, Saint Petersburg, Russia., Ryazantsev MN; Institute of Chemistry, Saint Petersburg State University, 198504, Saint Petersburg, Russia; Institute of Biomedical Systems and Biotechnologies, Peter the Great St. Petersburg Polytechnic University, 195251, Saint Petersburg, Russia., Tikhonov DB; Sechenov Institute of Evolutionary Physiology and Biochemistry of RAS, 194223, Saint Petersburg, Russia.
Jazyk: angličtina
Zdroj: European journal of pharmacology [Eur J Pharmacol] 2023 Jan 05; Vol. 938, pp. 175448. Date of Electronic Publication: 2022 Dec 05.
DOI: 10.1016/j.ejphar.2022.175448
Abstrakt: 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 IC 50 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.
Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest.
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Databáze: MEDLINE
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