TY - JOUR

T1 - Optical Control of N-Methyl-D-aspartate Receptors by Azobenzene Quaternary Ammonium Compounds

AU - Nikolaev, Maxim V

AU - Strashkov, Daniil M

AU - Ryazantsev, Mikhail N

AU - Tikhonov, Denis B

N1 - Funding Information: This study was supported by the Russian Foundation for Basic Research grant 20-04-00218 (to M.V.N.). D.M.S. and M.N.R. were supported by the Russian Foundation for Basic Research grant 20-315-90052. Analysis of the synthesized compounds was performed at the research park of St. Petersburg State University Center for Chemical Analysis and Materials Research. Publisher Copyright: ©

PY - 2021/9/15

Y1 - 2021/9/15

N2 - 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 IC50 values of 10 and 5 μM, respectively. Light-induced transformation of DENAQ and DMNAQ to their cis forms caused the IC50 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-3-hydroxy-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.

AB - 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 IC50 values of 10 and 5 μM, respectively. Light-induced transformation of DENAQ and DMNAQ to their cis forms caused the IC50 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-3-hydroxy-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.

KW - DENAQ

KW - NMDA receptor

KW - AMPA receptor

KW - photoswitchable action

KW - inhibition

KW - PHOTOCHROMIC AGONIST

KW - GLUTAMATE RECEPTORS

KW - VISUAL RESPONSES

KW - ION CHANNELS

KW - VOLTAGE

KW - PHOTOSWITCH

KW - CALCIUM

KW - alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid

KW - Rats

KW - Receptors, N-Methyl-D-Aspartate

KW - Animals

KW - Azo Compounds

KW - Quaternary Ammonium Compounds/pharmacology

KW - Receptors, AMPA

UR - https://pubs.acs.org/doi/10.1021/acschemneuro.1c00310

UR - http://www.scopus.com/inward/record.url?scp=85115192709&partnerID=8YFLogxK

UR - https://www.mendeley.com/catalogue/55c46d7c-dc6f-32a3-9918-853cf2e7f519/

U2 - 10.1021/acschemneuro.1c00310

DO - 10.1021/acschemneuro.1c00310

M3 - статья

C2 - 34469111

VL - 12

SP - 3347

EP - 3357

JO - ACS Chemical Neuroscience

JF - ACS Chemical Neuroscience

SN - 1948-7193

IS - 18

ER -