Optical Control of N-Methyl-d-aspartate Receptors by Azobenzene Quaternary Ammonium Compounds

Abstract

Azobenzene-based quaternary ammonium compounds provide optical control of ion channels and are considered promising agents for regulation of neuronal excitability and for restoration of the photosensitivity of retinal cells. However, the selectivity of the action of these compounds remains insufficiently known. We studied the action of DENAQ (diethylamine-azobenzene-quaternary ammonium) and DMNAQ (dimethylamine-azobenzene-quaternary ammonium) on ionotropic glutamate receptors in rat brain neurons. In the dark, both compounds applied extracellularly caused fast and reversible inhibition of NMDA (N-methyl-D-aspartate) receptor-mediated currents with IC 50 values of 10 and 5 μM, respectively. Light-induced transformation of DENAQ and DMNAQ to their cis forms caused the IC 50 values to increase to 30 and 27 μM, respectively. Detailed analysis of this action revealed a complex nature consisting of fast inhibitory and slower potentiating effects. The AMPA (α-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid) receptors were only weakly affected independently on illumination. We conclude that, in addition to their long-lasting intracellular action, which persists after washout, azobenzene-based quaternary ammonium compounds should affect glutamatergic transmission and synaptic plasticity during treatment. Our findings also extend the list of soluble photoswitchable inhibitors of NMDA receptors. While the site(s) and mechanisms of action are unclear, the effect of DENAQ demonstrates strong pH dependence. At acidic pH values, DENAQ potentiates both NMDA and AMPA receptors.

Reversible inhibition of GluN2B-containing NMDA receptors with anin situred-shifted, photoswitchable antagonist

“…A large number of soluble, photoswitchable ligands have been currently developed for many different targets including receptors, ion channels and enzymes (see, for instance, refs (40,42,48,83). In iGluRs, the large majority of previously developed photoswitchable compounds are competitive agonists and antagonists (82,(85)(86)(87)(88), with a few compounds targeting the ion channel pore (87,89,90). However, none of these compounds display subtype selectivity.…”

Recent Development of Photoresponsive Liposomes Based on Organic Photosensitizers, Au Nanoparticles, and Azobenzene Derivatives for Nanomedicine

“…This means that as liposomes in nanomedicine applications, azobenzene derivatives do not intersect directly with therapeutic processes such as tumor ablation but turn out to be photoswitching tools that assist this process. 123,124 In the pursuit of reversible release control studies, azobenzene derivatives hold unlimited fascination.…”

“…That is because the photoresponse mechanism of azobenzene derivatives in the liposome category is largely independent of temperature but rather exhibits a reversible change in physical structure. This means that as liposomes in nanomedicine applications, azobenzene derivatives do not intersect directly with therapeutic processes such as tumor ablation but turn out to be photoswitching tools that assist this process. , In the pursuit of reversible release control studies, azobenzene derivatives hold unlimited fascination.…”

Light-Sensitive Open Channel Block of Ionotropic Glutamate Receptors by Quaternary Ammonium Azobenzene Derivatives

“…We recently found that DENAQ and related compounds strongly affect ionotropic glutamate receptors of the NMDA type [ 32 , 33 ]. Unlike its action on voltage-gated channels, which is long-lasting and requires accumulation inside the cells, DENAQ causes a rapid photoswitchable inhibition of NMDA receptors during extracellular application.…”