Light-activated drug confirms a mechanism of ion channel blockade

Lester, Henry A.; Krouse, Mauri E.; Nass, Menasche M.; Wassermann, Norbert H.; Erlanger, Bernard F.

doi:10.1038/280509a0

Cited by 53 publications

(41 citation statements)

References 24 publications

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“…Interestingly, the flash-induced blockade in a given trans-EW-1 solution is temporarily much greater than the steady-state blockade in a nearly pure cis-EW-1 solution of equal concentration (64). Most of the blockade disappears with a time constant of about 300 msec.…”

Section: (86)mentioning

confidence: 92%

Physiological and Pharmacological Manipulations with Light Flashes

Lester¹,

Nerbonne²

1982

Annu. Rev. Biophys. Bioeng.

115

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Section: (86)mentioning

confidence: 92%

Physiological and Pharmacological Manipulations with Light Flashes

Lester¹,

Nerbonne²

1982

Annu. Rev. Biophys. Bioeng.

115

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“…Alternatively, inhibitors can be photogenerated, as has been shown by Lester et al. (7) in their studies of ion-channel blockade mechanisms. These ideas were taken further by Kaplan et al (8), who synthesized a y-phosphate ester of ATP, P3-1-(2-nitro)phenylethyladenosine 5'-triphosphate (I), which they called caged ATP.…”

mentioning

confidence: 99%

A new approach to time-resolved studies of ATP-requiring biological systems; laser flash photolysis of caged ATP.

McCray¹,

Kihara²,

Trentham³

1980

Proc. Natl. Acad. Sci. U.S.A.

231

192

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2-Nitrobenzyl derivatives have been used for several years as photolabile protecting groups in synthetic organic chemistry. Recently, P3-1(2-nitro)phenylethyladenosine 5'-triphosphate "caged ATP," was synthesized and its photolysis was shown to generate ATP in situ. This and related reactions have great potential for structural and kinetic studies of both intact and soluble biological systems and it is thus important to define the kinetic characteristics of the photolytic reaction. Caged ATP (2.5 mM) was photolyzed at 347 nm by a single 30-nsec pulse from a frequency-doubled ruby laser of 25 mJ energy to generate 500 .M ATP. The kinetics of the overall reaction were determined by monitoring the kinetics of ATP-induced dissociation of actomyosin, a reaction of known kinetic characteristics. Release of 500 IAM ATP was found to be controlled by a process having a rate constant of 2.2 X log0H+J sec-1 at 220C at pH 5.8-9.5, which corresponds to 220 sec-at pH 7. This process is believed to be the breakdown of an aci-nitro compound, which was identified on the basis of its spectral properties and the photochromicity of related 2-nitrobenzyl compounds. Photodissociation of carbon monoxide and dioxygen from hemoglobin (1, 2) is an important tool for analysis of hemoglobin functions. It would be valuable if a similar approach could be developed to encompass biological reactions in general. In principle, it should be possible to generate photochemically reactants such as metabolites from biologically inert photolyzable compounds. This would allow us to study intact macromolecular systems in which limitations arise because of the difficulty of introducing reactants to their sites of reaction in a time shorter than the characteristic time of the reaction under investigation.First steps toward this goal of photochemical deprotection have been reviewed by Knowles (3). These include the generation of inorganic phosphate from 3-nitrophenyl phosphate by Havinga et al. (4) (5) and Engels and Schlaeger (6), who described the synthesis of photolabile amino acid, peptide, and cyclic AMP precursors and suggested possible applications of their methods. Alternatively, inhibitors can be photogenerated, as has been shown by Lester et al. (7) in their studies of ion-channel blockade mechanisms. These ideas were taken further by Kaplan et al. (8), who synthesized a y-phosphate ester of ATP, P3-1-(2-nitro)phenylethyladenosine 5'-triphosphate (I), which they called caged ATP. They showed that caged ATP was inert toward the sodium pump, could be incorporated into vesicles and, on continuous irradiation (on the time scale of seconds), formed ATP. In the work described here, the amount and rate of ATP generation after laser flash photolysis of caged ATP was measured to determine the potential of caged ATP as an ATP precursor for use in kinetic studies of intact biological systems. It is shown that the energy per pulse from a frequency doubled ruby laser generates ATP in sufficient concentration for biological studies. By using a well ...

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“…After removal of the protecting group from small photocaged molecules by long-wavelength UV (365 nm) irradiation and photolysis, the channel becomes responsive to the pH of the environment [202]. Furthermore, UV-irradiation of azobenzene molecules promotes the trans-cis isomerization at the central double bond, resulting in considerable changes in geometry and polarity [203,204]. Azobenzene is known to exist in cis (loose spacing) and trans (tight spacing) configurations in dark and light conditions, respectively [205,206].…”

Section: Non-fluorescent Prodrugs/converted Into Fluorescent Active Dmentioning

confidence: 99%

Fluorescent Dyes Used in Polymer Carriers as Imaging Agents in Anticancer Therapy

Miksa¹

2016

Med chem (Los Angeles)

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This review highlights the role of fluorescent dyes as active "molecular photoswiches" focusing on the application in bioimaging and anticancer therapies in the field of therapeutic delivery. The author describes the development of prodrugs targeted to specific cell types and polymeric nanocarriers (capsules, micelles and silica nanoparticles) used as fluorescent probes which offer advantages in the integration of "smart" features of fluorescent dyes into synthetic materials. The incorporation of biologically responsive components that cleave upon changes in pH or light irradiation is fundamental to the successful design of such carriers with capabilities to load and release therapeutics specifically at a target site.

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Light-activated drug confirms a mechanism of ion channel blockade

Cited by 53 publications

References 24 publications

Physiological and Pharmacological Manipulations with Light Flashes

Physiological and Pharmacological Manipulations with Light Flashes

A new approach to time-resolved studies of ATP-requiring biological systems; laser flash photolysis of caged ATP.

Fluorescent Dyes Used in Polymer Carriers as Imaging Agents in Anticancer Therapy

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