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Nicoleta Dobri, Qiong Qin, Jian Kong, Rando Allikmets, Janet Sparrow, Konstantin Petrukhin; Evaluation of different classes of RBP4 antagonists as potential treatments for AMD. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1703.
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Pharmacological inhibition of the retinol-induced interaction of Retinol-Binding Protein 4 (RBP4) with transthyretin (TTR) in the serum may decrease the uptake of serum retinol to the retina and reduce formation of lipofuscin bisretinoids. A1120 is non-retinoid RBP4 ligand capable of antagonizing retinol-induced RBP4-TTR interaction. Here we present characterization of A1120 and other classes of RBP4 agonists in a battery of in vivo and in vitro assays.
RBP4 binding potency, ability to antagonize RBP4-TTR interaction and compound specificity were compared for the representatives of different classes of RBP4 antagonists. Specificity of compounds was confirmed in in vitro assays probing the compound effect on the activity of protein targets capable of binding different types of retinoids. The in vivo effect of compound administration on levels of serum RBP4, visual cycle retinoids, lipofuscin bisretinoids, and retinal visual function was evaluated using a combination of biochemical and electrophysiological techniques
We documented significant reduction of serum RBP4 in response to administration of RBP4 antagonists representing different structural classes. Compound administration induced partial depletion of visual cycle retinoids and significant inhibition of bisretinoid accumulation in the mouse model of enhanced lipofuscinogenesis while no significant changes in kinetics of dark adaptation after the photobleach were evident following long-term compound dosing.
Medicinal chemistry optimization in selected structural series may yield drug candidates with optimized potency and improved pharmacokinetic characteristics which could allow their use in treatment of dry AMD, Stargardt disease and other conditions characterized by excessive lipofuscin accumulation.
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