Vascular actions of ‘caged’ phenylephrine analogs depend on the structure and site of attachment of the 2-nitrobenzyl group

Boyle, Walter A.; Muralidharan, S.; Maher, Gail M.; Nerbonne, Jeanne M.

doi:10.1016/s1011-1344(97)00108-5

Cited by 4 publications

(2 citation statements)

References 13 publications

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“…Design of Target Structures. Targets were designed by consideration of the photolytic reactivity of related structures, for example, 2-nitrobenzyl-caged tyrosine, serotonin, and phenylephrine . Caged tyrosine is cleaved upon exposure to 350 nm light for 12 h. 4,5-Dimethoxy-2-nitrobenzyl-caged serotonin releases the neurotransmitter upon excitation by 308 or 337 nm laser pulses.…”

Section: Resultsmentioning

confidence: 99%

“…The 4,5-dimethoxy groups in a caged nitrobenzyl phenylephrine derivative increases the maximum UV absorption wavelength from 272 to 330 nm and suggests electron-rich nitrobenzyl groups can be cleaved from caged compounds at longer wavelengths, an advantage when working in biological systems. Dimethoxy substitution of caged nitrobenzyl phenylephrine also increases the rate of photolysis relative to the unsubstituted nitrobenzyl phenylephrine analogue 22a. This observation supports that electron-releasing benzyl substituents promote photolytic cleavage of 2-nitrobenzyl phenolic ethers.…”

Section: Resultsmentioning

confidence: 99%

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Model Compounds of Caged Capsaicin: Design, Synthesis, and Photoreactivity

Katritzky¹,

Xu²,

Vakulenko³

et al. 2003

J. Org. Chem.

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Molecules were prepared with substituted nitrobenzyl groups covalently bonded to N-(4-hydroxy-3-methoxybenzyl)acetamide (2) by ether or carbonate linkages. These compounds decomposed under irradiation at 363 nm. Those with carbonate linkages decomposed at slower rates than those with ether linkages. Molecules with dimethoxy-substituted benzyl groups decomposed more slowly than monomethoxy-substituted benzyl groups due to the electronic characteristics of the benzylic carbon.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Model Compounds of Caged Capsaicin: Design, Synthesis, and Photoreactivity

Katritzky¹,

Xu²,

Vakulenko³

et al. 2003

J. Org. Chem.

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Photoactivatable Prodrugs of Highly Potent Duocarmycin Analogues for a Selective Cancer Therapy

Tietze

Müller

Duefert

et al. 2012

Chemistry A European J

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A main problem of common cancer chemotherapy is the occurrence of severe side effects caused by insufficient selectivity of the applied drugs. A possible concept to overcome this limitation is light-driven prodrug monotherapy. The synthesis as well as photochemical and biological evaluation of new photoactivatable prodrugs is described. Best results were obtained with prodrug (S,S)-7a. The photochemical labile protecting groups in (S,S)-7a can easily be removed by irradiation with UV-A light in 30 min with a power of only 2 J cm(-2). The determination of the in vitro cytotoxicity by using an HTCFA-test reveals a QIC(50) value of 8200 and the prodrug is more than two million times less cytotoxic than the corresponding seco-drug (-)-(S,S)-5 with an IC(50) value of about 110 fM. The big therapeutic window makes (S,S)-7a very suitable for its use in selective cancer therapy.

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Relevance of rhodopsin studies for GPCR activation

Deupí

2014

Biochimica et Biophysica Acta (BBA) - Bioenergetics

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Rhodopsin, the dim-light photoreceptor present in the rod cells of the retina, is both a retinal-binding protein and a G protein-coupled receptor (GPCR). Due to this conjunction, it benefits from an arsenal of spectroscopy techniques that can be used for its characterization, while being a model system for the important family of Class A (also referred to as "rhodopsin-like") GPCRs. For instance, rhodopsin has been a crucial player in the field of GPCR structural biology. Until 2007, it was the only GPCR for which a high-resolution crystal structure was available, so all structure-activity analyses on GPCRs, from structure-based drug discovery to studies of structural changes upon activation, were based on rhodopsin. At present, about a third of currently available GPCR structures are still from rhodopsin. In this review, I show some examples of how these structures can still be used to gain insight into general aspects of GPCR activation. First, the analysis of the third intracellular loop in rhodopsin structures allows us to gain an understanding of the structural and dynamic properties of this region, which is absent (due to protein engineering or poor electron density) in most of the currently available GPCR structures. Second, a detailed analysis of the structure of the transmembrane domains in inactive, intermediate and active rhodopsin structures allows us to detect early conformational changes in the process of ligand-induced GPCR activation. Finally, the analysis of a conserved ligand-activated transmission switch in the transmembrane bundle of GPCRs in the context of the rhodopsin activation cycle, allows us to suggest that the structures of many of the currently available agonist-bound GPCRs may correspond to intermediate active states. While the focus in GPCR structural biology is inevitably moving away from rhodopsin, in other aspects rhodopsin is still at the forefront. For instance, the first studies of the structural basis of disease mutants in GPCRs, or the most detailed analysis of cellular GPCR signal transduction networks using a systems biology approach, have been carried out in rhodopsin. Finally, due again to its unique properties among GPCRs, rhodopsin will likely play an important role in the application of X-ray free electron laser crystallography to time-resolved structural biology in membrane proteins. Rhodopsin, thus, still remains relevant as a model system to study the molecular mechanisms of GPCR activation. This article is part of a Special Issue entitled: Retinal Proteins-You can teach an old dog new tricks.

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Vascular actions of ‘caged’ phenylephrine analogs depend on the structure and site of attachment of the 2-nitrobenzyl group

Cited by 4 publications

References 13 publications

Model Compounds of Caged Capsaicin: Design, Synthesis, and Photoreactivity

Model Compounds of Caged Capsaicin: Design, Synthesis, and Photoreactivity

Photoactivatable Prodrugs of Highly Potent Duocarmycin Analogues for a Selective Cancer Therapy

Relevance of rhodopsin studies for GPCR activation

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