TOA EIYO (Japan)

Exogenous and endogenous cholesterol oxidation products (COPs) perturb various metabolic processes, and thereby they may induce various homeostasis-related disorders. Here, we observed that procyanidin-rich dietary apple polyphenol (APP) from unripe apples alleviates the perturbation of lipid metabolism by decreasing the exogenous COP levels in rats. Dietary COPs may be the greatest source of COPs found in the human body. Rats (4 weeks of age) were fed AIN-purified diets containing 0.3% COPs supplemented with 0.5 or 2.5% APP for 3 weeks. Dietary APP alleviated the growth inhibition action of the exogenous COPs. The modulations of the liver lipid profile by COPs remained unchanged. However, serum total cholesterol, high-density lipoprotein cholesterol, and triglyceride levels increased following the intake of dietary APP. Further, dietary APP inhibited the increase in lipid peroxide levels in the liver and serum by COPs. The activity of hepatic Delta6 desaturase was lowered by dietary APP in a dose-dependent manner, although exogenous COPs generally increased the activity of this enzyme. In keeping with this observation, Delta6 desaturation indices in the phospholipids and cholesteryl esters of the liver and serum lipids were lower in the APP-fed groups than those in the control group. Dietary APP also promoted the excretion of exogenous COPs, cholesterol, and acidic steroids in feces. Therefore, the inhibition of intestinal absorption of COPs may partly contribute to the alleviation of the perturbation of lipid metabolism and lipid peroxidation levels. Thus, APP may be an important removal agent of exogenous toxic material such as COPs contained in processed or fast foods.

Sphingosine 1-phosphate (S1P) receptors are G-protein-coupled receptors. Among the five identified subtypes S1P1-5, the S1P3 receptor expressed on vascular endothelial cells has been shown to play an important role in cell proliferation, migration, and inflammation. A pharmacophore-based database search was used to identify a potent scaffold for an S1P3 receptor antagonist by common feature-based alignment and further validated using the Güner-Henry (GH) scoring method. Assumed excluded volumes were merged into this model to evaluate the steric effect with the S1P3 receptor. Three commercially available compounds were identified as S1P3 receptor antagonists, with IC50 values <5 microM. The synthesis of further derivatives revealed that the 3,4-dialkoxybenzophenone scaffold is a potent component of an S1P3 receptor antagonist. Our results indicate that pharmacophore-based design of S1P3 receptor antagonists can be used to expand the possibility of structural modification through scaffold-hopping based on a database search.

Sphingosine-1-phosphate (S1P) is an intracellular second messenger and an extracellular mediator through endothelial differentiation gene (EDG) receptors, which are a novel class of G-protein-coupled receptors. Although EDG has attracted much attention because of its various roles, no selective agonists or antagonists have yet been developed. This could account for the delay in clarifying the physiological roles of members of the EDG family. Because precise structural information on EDG receptors is not yet available, pharmacophore models were generated based on structural information for S1P using the rational drug design software Catalyst. Novel antagonists, 2-alkylthiazolidine-4-carboxylic acids, were retrieved from a three-dimensional database search using the pharmacophore models, and these showed activity for EDG3. On the basis of their nonphosphoric acid structure, more potent antagonists, 2-(m- or p-heptylphenyl)thiazolidine-4-carboxylic acid, were developed.

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