Synthetic Photoswitchable Neurotransmitters Based on Bridged Azobenzenes

Abstract

Photoswitchable neurotransmitters of ionotropic kainate receptors were synthesized by tethering a glutamate moiety to disubstituted C2-bridged azobenzenes, which were prepared through a novel methodology that allows access to diazocines with higher yields and versatility. Because of the singular properties of these photochromes, photoisomerizable compounds were obtained with larger thermal stability for their inert cis isomer than for their biologically activity trans state. This enabled selective neuronal firing upon irradiation without background activity in the dark.

Two-Photon Excitation of Azobenzene Photoswitches for Synthetic Optogenetics

“…Notably, this photoswitch could be activated by 2PE (Table 1). In a subsequent report, the authors estimated its 2P-absopriton cross section and suggest it to be~five times higher than that of the parent photoswitch (MAG2p, σ2 = 56 GM [72] at 850 nm, Table 1). The authors go on to show that, when coupled to a glutamate receptor (LiGluR [63]) optimal 2P-responses are obtained at 900 nm.…”

“…The second approach, the C2-bridged azobenzene, also show a significant red-shifted absorption spectrum of the -trans isomer (λ max > 540 nm) [72,74,81], implying an increased 2P-absorption cross section [41], but with a much more favorable (i.e., slower) thermal relaxation rate (on the order of minutes at room temperature in aqueous solution) than methoxy meta-substitutions. The drawback of the molecule is that the -cis state is the more thermodynamically stable form.…”

“…An additional drawback is that the stable -cis isomer poorly absorbs red light and isomerization to -trans requires UV to near UV illumination. Recently, two trans-active diffusible photoswitches were designed based on a C2-bridged azobenzene, denoted locked-azobenzene (LAB) [82] or Glu_brAzo [72]. Both photoswitches bear a glutamate moiety as ligand, thus intended for activation of glutamate receptors, and exhibit highly similar structural and spectral properties (Figure 3).…”

Visible-light-driven photocontrol of the Trp-cage protein fold by a diazocine cross-linker

“…In fact, the PSS of the switch cage compares well with the few published PSSs of diazocine derivatives in aqueous solution that range between 16% and 60% of transisomer. [53][54][55][56] Although the conditions differ in pH, buffer and DMSO content, it appears that the PSSs of ethylene bridged diazocines § in aqueous environment are generally lower than the PSS of the parent diazocine 21,22 in organic solvents (>90% trans-species in n-hexane). In addition to the solvent effect, in cis-SC the folding free energy of the Trp-cage has to be overcome in order to unfold the miniprotein upon cis → trans-isomerization which also may lower the PSS.…”

Effiziente Umwandlung von Licht in chemische Energie: Gerichtete, chirale Photoschalter mit sehr hohen Quantenausbeuten

“…Darüber hinaus sind Diazocine 2 in ihrer sperrigeren cis-Konfiguration thermodynamisch stabiler, was bei Anwendung in der Photopharmakologie und dem Mechanosensing von Vorteil ist. [19][20][21][22] Jedoch sind weder Azobenzol 1 noch Diazocin 2 gerichtete Schalter und kçnnen daher keine gerichtete Bewegung induzieren (Abbildung 2 a,b, gebogene Pfeile bei 3 und 4 zeigen die Richtung der molekularen Bewegung während der Isomerisierung). Die Einführung zusätzlicher Brücken in das tricyclische Diazocinsystem sollte die konformationellen Bewegungen weiter verringern und eine gerichtete Bewegung beim Schalten ermçglichen.…”