Degenerative eye diseases are the most common causes of untreatable blindness. Accumulation of lipofuscin (granular deposits) in the retinal pigment epithelium (RPE) is a hallmark of major degenerative eye diseases such as Stargardt disease, Best disease, and age-related macular degeneration. The intrinsic reactivity of vitamin A leads to its dimerization and to the formation of pigments such as A2E, and is believed to play a key role in the formation of ocular lipofuscin. We sought a clinically pragmatic method to slow vitamin A dimerization as a means to elucidate the pathogenesis of macular degenerations and to develop a therapeutic intervention. We prepared vitamin A enriched with the stable isotope deuterium at carbon twenty (C20-D 3 -vitamin A). Results showed that dimerization of deuterium-enriched vitamin A was considerably slower than that of vitamin A at natural abundance as measured in vitro. Administration of C20-D 3 -vitamin A to wild-type rodents with no obvious genetic defects in vitamin A processing, slowed A2E biosynthesis. This study elucidates the mechanism of A2E biosynthesis and suggests that administration of C20-D 3 -vitamin A may be a viable, long-term approach to retard vitamin A dimerization and by extension, may slow lipofuscin deposition and the progression of common degenerative eye diseases.

Accumulation of fluorescent metabolic byproducts of the visual (retinoid) cycle is associated with photoreceptor and retinal pigment epithelial cell death in both Stargardt disease and atrophic (nonneovascular) age-related macular degeneration (AMD). As a consequence of this observation, small molecular inhibitors of enzymes in the visual cycle were recently tested in clinical trials as a strategy to protect the retina and retinal pigment epithelium in patients with atrophic AMD.To address the clinical translational needs for therapies aimed at both diseases, a workshop organized by the Foundation Fighting Blindness was hosted by the Department of Pharmacology at Case Western Reserve University on February 17, 2017, at the Tinkham Veale University Center, Cleveland, OH, USA. Invited speakers highlighted recent advances in the understanding of the pathophysiology of Stargardt disease, in terms of its clinical characterization and the development of endpoints for clinical trials, and discussed the comparability of therapeutic strategies between atrophic age-related macular degeneration (AMD) and Stargardt disease. Investigators speculated that reducing the concentrations of visual cycle precursor substances and/or their byproducts may provide valid therapeutic options for the treatment of Stargardt disease. Here we review the workshop's presentations in the context of published literature to help shape the aims of ongoing research endeavors and aid the development of therapies for Stargardt disease.

The primary event in mammalian vision is a light-initiated cisto-trans isomerization of the retinal chromophore bound, via a protonated Schiff base, to a lysine residue in the opsin apoprotein ( Figure 1A). 1 This isomerization activates the protein which triggers a series of events resulting in a signal to the brain. This has been a basic tenet of our understanding of vision. Rod-rhodopsin, the opsin-retinal complex responsible for night vision, is a G-proteincoupled receptor, activated by light with an absorbance maximum at 500 nm. As the absorption from rhodopsin is minute above 600 nm, the pigment is not believed to be involved in vision at longer wavelengths.It has been proposed that the visual signal transduction pathway in a species of deep-sea fish involves the use of photosensitizers. 2 Molecules derived from chlorophyll 650 are thought to absorb longer-wavelength light and transfer the gained energy to shorterwavelength visual pigments ( Figure 1B), thus adding an extra step to their transduction pathway. This is based on the observations that: (i) the fish only possess visual pigments with λ max e 545 nm, (ii) bleaching of its 545 nm pigment with 671 nm light is faster than bleaching with 654 nm light, and (iii) chlorophyll derivatives which have strong absorbances centered at 665 nm have been isolated along with the 545 nm pigment. A triplet-triplet energytransfer mechanism from the chlorophyll 650 derivatives to the 545 nm pigment has been speculated. 2 Enhanced visual sensitivity is reported as a common side effect in patients exposed to porphyrins during photodynamic therapy. 3 In related photosynthetic systems found in plants, carotenoids are believed to act as quenchers of chlorophylls and singlet oxygen, in addition to their primary roles as light-harvesting complexes. 4 The quenching involves triplet-state energy transfer from chlorophyll to carotenoid. 4b To expand rhodopsin sensitivity into the near-IR we have investigated the bleaching of bovine rhodopsin upon exposure to λ max ) 675 nm light in the presence of various chromophores which are potential photosensitizers with strong absorptions around 665 nm. We report rate enhancements on the order of up to 3 times compared to that for the bleaching of rhodopsin alone with λ max ) 675 nm light.In all experiments the bleaching rates of bovine rhodopsin were measured using UV-vis spectroscopy by monitoring the absorbance at 500 nm corresponding to that for the Schiff base. A 0.009 mmol solution of bovine rhodopsin (90% in ROS suspension) solublized in 5% dodecyl--D-maltoside 5 in phosphate-buffered saline was used for all bleaching experiments. The curve marked rhodopsin in Figure 2 depicts a bleaching rate set to 1.0, for the initial 30 min of bleaching of bovine rhodopsin, with λ max ) 675 nm light at 25°C.

Oxazolidinone-functionalized enecarbamates react stereoselectively with singlet oxygen to give methyldesoxybenzoin (MDB) in moderate to high enantiomeric excess. The stereochemical outcome depends on the E/Z substrate geometry, temperature, and solvent variables. The analysis of the differential activation parameters suggests a large contribution from the entropy term in determining the enantioselectivity. We demonstrate the utility of the temperature and solvent variables in determining the degree of the photochemical kinetic resolution of the enecarbamates; for example, in the photooxygenation at −70 °C in methanol, MDB may be obtained in methanol.