A Photochromic Agonist for μ‐Opioid Receptors

Schönberger, Matthias; Trauner, Dirk

doi:10.1002/anie.201309633

Cited by 120 publications

(135 citation statements)

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“…60 The tetra ortho substitution pattern has proven very versatile. We developed extended versions of the photoswitch that show enhanced end-to-end distance changes upon photoswitching (23,24) and can be used to control peptide conformation. 35 Using Trauner's approach to synthesizing tethered ligands for glutamate receptors, we made tetra-ortho-chloro MAG (25), which Isacoff's group showed could be used to control Glu receptor activity with red light in living cells.…”

Section: ■ Tetra-ortho-methoxy Substitutionmentioning

confidence: 99%

Red-Shifting Azobenzene Photoswitches for in Vivo Use

et al. 2015

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Recently, there has been a great deal of interest in using the photoisomerization of azobenzene compounds to control specific biological targets in vivo. These azo compounds can be used as research tools or, in principle, could act as optically controlled drugs. Such "photopharmaceuticals" offer the prospect of targeted drug action and an unprecedented degree of temporal control. A key feature of azo compounds designed to photoswitch in vivo is the wavelength of light required to cause the photoisomerization. To pass through tissue such as the human hand, wavelengths in the red, far-red, or ideally near infrared region are required. This Account describes our attempts to produce such azo compounds. Introducing electron-donating or push/pull substituents at the para positions delocalizes the azobenzene chromophore and leads to long wavelength absorption but usually also lowers the thermal barrier to interconversion of the isomers. Fast thermal relaxation means it is difficult to produce a large steady state fraction of the cis isomer. Thus, specifically activating or inhibiting a biological process with the cis isomer would require an impractically bright light source. We have found that introducing substituents at all four ortho positions leads to azo compounds with a number of unusual properties that are useful for in vivo photoswitching. When the para substituents are amide groups, these tetra-ortho substituted azo compounds show unusually slow thermal relaxation rates and enhanced separation of n-π* transitions of cis and trans isomers compared to analogues without ortho substituents. When para positions are substituted with amino groups, ortho methoxy groups greatly stabilize the azonium form of the compounds, in which the azo group is protonated. Azonium ions absorb strongly in the red region of the spectrum and can reach into the near-IR. These azonium ions can exhibit robust cis-trans isomerization in aqueous solutions at neutral pH. By varying the nature of ortho substituents, together with the number and nature of meta and para substituents, long wavelength switching, stability to photobleaching, stability to hydrolysis, and stability to reduction by thiols can all be crafted into a photoswitch. Some of these newly developed photoswitches can be used in whole blood and show promise for effective use in vivo. It is hoped they can be combined with appropriate bioactive targets to realize the potential of photopharmacology.

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Section: ■ Tetra-ortho-methoxy Substitutionmentioning

confidence: 99%

Red-Shifting Azobenzene Photoswitches for in Vivo Use

et al. 2015

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“…This approach involves genetic manipulation of the protein so that a reactive cysteine residue can be placed in a specific site on the receptor. A second method involves a small molecule ligand that contains a head group that resembles a known receptor agonist or antagonist [74,[79][80][81][82][83][84][85]. The affinity is light dependent, the conformation of one isomer interferes with binding and/or activation and the other permits it.…”

Section: Photoswitchable Ion Channels and Receptorsmentioning

confidence: 99%

Photochromic Materials in Biochemistry

Wilson

Branda

2016

Photochromic Materials: Preparation, Properties and Applications

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“…Application of such compounds (potential photo-analgesics) can allow an optical control of μ-opioid receptors. The first compound was an azobenzene derivative of fentanyl (photofentanyl-2 or PF2) [4]. Fentanyl is a potent synthetic μ-opioid receptor agonist.…”

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confidence: 99%

“…The GPCR's photo-switchable compound PF2 was produced and tested in human μ-opioid receptor transfected into HEK293t cells with the G-protein-coupled inward rectifier channels (GIRK1 and GIRK2) [4]. The optimal photo-switching properties of PF2 were achieved at concentration of 25 mm.…”

mentioning

confidence: 99%

“…Hence, switching from 360 nm to blue light initiated a quick potassium influx via GIRK channels that was terminated by 360 nm light, which could abolish the activation of μ-receptors. Introduction of PF2 not only opened up a new road toward potential use of photo-analgesics in the future, but also to demonstrate that photo-switchable compounds can also be used to further investigate opioid receptors [3,4].…”

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confidence: 99%

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