Development of a quaternary ammonium photoswitchable antagonist of NMDA receptors

Maxim V Nikolaev; Daniil M Strashkov; Mikhail N Ryazantsev; Denis B Tikhonov

doi:10.1016/j.ejphar.2022.175448

Development of a quaternary ammonium photoswitchable antagonist of NMDA receptors

Eur J Pharmacol. 2023 Jan 5:938:175448. doi: 10.1016/j.ejphar.2022.175448. Epub 2022 Dec 5.

Authors

Maxim V Nikolaev¹, Daniil M Strashkov², Mikhail N Ryazantsev³, Denis B Tikhonov⁴

Affiliations

¹ Sechenov Institute of Evolutionary Physiology and Biochemistry of RAS, 194223, Saint Petersburg, Russia. Electronic address: fmedfstud@gmail.com.
² Saint Petersburg National Research Academic University of the Russian Academy of Sciences, 194021, Saint Petersburg, Russia.
³ 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.
⁴ Sechenov Institute of Evolutionary Physiology and Biochemistry of RAS, 194223, Saint Petersburg, Russia.

PMID: 36470444
DOI: 10.1016/j.ejphar.2022.175448

Abstract

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.

Keywords: Inhibition; NMDA receptor; Photopharmacology; Photoswitches.

MeSH terms

Ammonium Compounds* / pharmacology
Animals
Azo Compounds / chemistry
Azo Compounds / pharmacology
Rats
Receptors, Glutamate
Receptors, N-Methyl-D-Aspartate* / antagonists & inhibitors

Substances

Ammonium Compounds
Azo Compounds
azobenzene
Receptors, Glutamate
Receptors, N-Methyl-D-Aspartate