Azo‐Propofols: Photochromic Potentiators of GABA<sub>A</sub> Receptors

Stein, Marco; Middendorp, Simon J.; Carta, Valentina; Pejo, Ervin; Raines, Douglas E.; Forman, Stuart A.; Sigel, Erwin; Trauner, Dirk

doi:10.1002/anie.201205475

Cited by 137 publications

(91 citation statements)

References 25 publications

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“…35 We also found that tetra-ortho-thioether groups (21) could be used to circumvent reduction while enhancing the molar absorption coefficient in the red region compared to the tetra-ortho-chloro species. 36 About the same time, Hecht's group synthesized the tetra-ortho-fluoro substituted species (22). 60 While this does not have the same degree of n−π* red shifting, it has an extraordinarily slow thermal cis-to-trans relaxation rate (years) so that it is truly bistable on biological time scales.…”

Section: ■ Tetra-ortho-methoxy Substitutionmentioning

confidence: 98%

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: 98%

Red-Shifting Azobenzene Photoswitches for in Vivo Use

et al. 2015

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“…Extension of propofol to the azobenzene AP-2 provided a photoswitch for the optical control of inhibitory GABA currents. 34 Amiloride and its more lipophilic congener phenamil are clinically used blockers of epithelial sodium channels (ENaC). Our photoswitchable version, PA-1, could be used to optically control the δβγ-isoform of these important channels.…”

Section: Accounts Of Chemical Researchmentioning

confidence: 99%

A Roadmap to Success in Photopharmacology

2015

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Light is a fascinating phenomenon that ties together physics, chemistry, and biology. It is unmatched in its ability to confer information with temporal and spatial precision and has been used to map objects on the scale of tens of nanometers (10(-8) m) to light years (10(16) m). This information, gathered through super-resolution microscopes or space-based telescopes, is ultimately funneled through the human visual system, which is a miracle in itself. It allows us to see the Andromeda galaxy at night, an object that is 2.5 million light years away and very dim, and ski the next day in bright sunlight at an intensity that is 12 orders of magnitude higher. Human vision is only one of many photoreceptive systems that have evolved on earth and are found in all kingdoms of life. These systems rely on molecular photoswitches, such as retinal or tetrapyrrols, which undergo transient bond isomerizations or bond formations upon irradiation. The set of chromophores that have been employed in Nature for this purpose is surprisingly small. Nevertheless, they control a wide variety of biological functions, which have recently been significantly increased through the rapid development of optogenetics. Optogenetics originated as an effort to control neural function with genetically encoded photoreceptors that use abundant chromophores, in particular retinal. It now covers a variety of cellular functions other than excitability and has revolutionized the control of biological pathways in neuroscience and beyond. Chemistry has provided a large repertoire of synthetic photoswitches with highly tunable properties. Like their natural counterparts, these chromophores can be attached to proteins to effectively put them under optical control. This approach has enabled a new type of synthetic photobiology that has gone under various names to distinguish it from optogenetics. We now call it photopharmacology. Here we trace our involvement in this field, starting with the first light-sensitive potassium channel (SPARK) and concluding with our most recent work on photoswitchable fatty acids. Instead of simply providing a historical account of our efforts, we discuss the design criteria that guided our choice of molecules and receptors. As such, we hope to provide a roadmap to success in photopharmacology and make a case as to why synthetic photoswitches, properly designed and made available through well-planned and efficient syntheses, should have a bright future in biology and medicine.

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“…They are important for signaling and neuronal function. There has been much progress in the field of light-controlled neuronal signaling, and these advances have extended to living cells and organisms [1,8,73,74]. The combination of synthetic photoswitches and naturally occurring receptor proteins has proved to be an effective means for rapidly and reversibly controlling channel function, and have aided in studying processes related to channel function.…”

Section: Photoswitchable Ion Channels and Receptorsmentioning

confidence: 99%

“…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%