Photocontrol of endogenous glycine receptors in vivo

Abstract

Glycine receptors (GlyRs) are indispensable to maintain excitatory/inhibitory balance in neuronal circuits controlling reflex and rhythmic motor behaviors. Here we have developed Glyght, the first GlyR ligand controlled with light. It is selective over other cys-loop receptors, active in vivo, and displays an allosteric mechanism of action. The photomanipulation of glycinergic neurotransmission opens new avenues to understand inhibitory circuits in intact animals, and to develop drug-based phototherapies. Photocontrol of endogenous glycine receptors in vivoGomila et al.

Optical Control of GABAA Receptors with a Fulgimide‐Based Potentiator

“…Although some GABA A R photoswitches have been reported based on azobenzene, this photochromic group displays several shortcomings: it provides incomplete photoconversion due to a substantial overlap of the absorption maxima of cis and trans isomers, and can alter the pharmacophore activity. Indeed, in all azobenzene derivatives of benzodiazepines (allosteric potentiators of GABA A R) this characteristic property is abolished, as found in the 7‐amino site of nitrazepam, which is reportedly tolerant of other substitutions . In addition, GABA A R photoswitches described so far are agonists or antagonists that interfere with endogenous neurotransmission, not pure modulators …”

Subunit-Specific Photocontrol of Glycine Receptors by Azobenzene-Nitrazepam Photoswitcher

“…The same docking protocol as for the calculations focused on the M2 helices of the pore was used. This strategy was recently used to uncover the putative binding site of another photochromic ligand, Glyght, to GlyRs (Gomila et al 2020).…”

Fulgazepam: A Fulgimide-Based Potentiator of GABAA Receptors

“…[3][4][5][6]20] Our quest for photochromic derivatives of benzodiazepines has led to the serendipitous identification of a pore blocker of GABAA receptors (Azo-NZ1) [21] , and a selective inhibitor of the structurally related glycine receptors (Glyght). [22] However, it has failed to preserve the allosteric potentiator profile of GABAARs that is characteristic of benzodiazepines. Azobenzenes have been successfully used as photochromic scaffolds for biological applications [21][22][23][24][25][26][27][28] due to their synthetic accessibility and their large change in geometry and dipole moment upon switching.…”

“…[22] However, it has failed to preserve the allosteric potentiator profile of GABAARs that is characteristic of benzodiazepines. Azobenzenes have been successfully used as photochromic scaffolds for biological applications [21][22][23][24][25][26][27][28] due to their synthetic accessibility and their large change in geometry and dipole moment upon switching. [3][4][5][6]20,29] However, several drawbacks limit their range of application.…”