Quantitative Structure-Activity Relatioships studies of antioxydant hexahydropyridoindoles and flavonoids derivatives

peer reviewedIn order to predict the antioxidant activity of 22 pinoline derivatives (1,2,3,4-tetrahydro-b-carbolines), two dimensional quantitative-structure activity relationships (2D-QSAR) analysis of 19 hexahydropiridoindoles and 12 flavonoids was realized. Five statistically significant models were obtained from randomly constituted training sets (21 compounds) and subsquently validated with the corresponding test sets (10 compounds). Antioxidant activity (pIC50) was correlated with 5 molecular descriptors calculated with the software DRAGON. The best predictive model (n = 21, q2 = 0.794, N = 2, r2 = 0.888, s = 0.157) could offer structural insights into the features conferring a strong antioxidant activity to compounds built from a pinoline scaffold prior to their synthesis

Homology modeling of the serotoninergic 5-HT2c receptor

Since its discovery, 5-hydroxytryptamine, more usually called serotonin, has been an elusive candidate as a major mood regulator. This capacity gives it a great importance in the treatment of depression. It is within this framework that our work takes place, as it is related more particularly to a new therapeutic class whose leader is agomelatine. This compound binds to the melatoninergic receptors and to the serotoninergic 5-HT2c receptor, giving rise to the MASSA concept (Melatonin Agonist and Selective Serotonin Antagonist). Like the majority of the serotoninergic receptors, the sub-type 5-HT2c is a G-protein coupled receptor (GPCR). The three-dimensional structure of 5-HT2c is not experimentally known, and we thus resorted to comparative homology modelling to build a model allowing us to study its interactions with agomelatine

Antioxydant activity of β-carboline derivatives in the LDL oxidation model

A series of b-carboline compounds were synthesized, starting from compound GWC22, their antioxidant activity was determined by inhibition of lipid peroxidation. The oxidation of LDL was induced in the presence of CuSO4 or 2,20-azobis(2-amidinopropane) dihydrochloride (AAPH). The protective actions of these compounds against the cytotoxicity were evaluated with lactate dehydrogenase (LDH) activity in bovine aortic endothelial cells (BAECs) and cellular vitality by measuring mitochondrial activity in the presence of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide). Most of compounds showed an higher antioxidant activity than GWC22 derivative (R = 1.6 for 5 mM CuSO4). The best antioxidant activities are phenolic and benzyloxy derivatives with ratio R = 1.9 to 2.8 for 1 mM CuSO4. These substances have protective actions and increase significantly the cell viability

Homology modeling of MT(1) and MT(2) receptors

Melatonin is a neurohormone synthesized and secreted mainly during the dark period of the circadian cycle by the pineal gland. It has already been proved to be involved in a number of chronobiological processes, most of them being mediated by its membranar receptors MT1 and MT2. Both are members of the GPCR class and, despite the interest they elicit, their 3D structure is still to be described. Models for both human MT1 and MT2 receptors have been constructed by homology modeling, using the X-ray structure of bovine rhodopsin as template. These models have been evaluated in terms of hydrophobic properties of the helices and refined to take into account the rearrangement of GPCRs necessary for their activation, thus leading to a putative activated model for each subtype

The RXR agonist bexarotene improves cholesterol homeostasis and inhibits atherosclerosis progression in a mouse model of mixed dyslipidemia

Objective - The activity of the antitumoral agent bexarotene (Targretin, Bexarotene) depends on its binding to the nuclear retinoid-X receptor (RXR) and subsequent transcriptional regulation of target genes. Through RXR activation, bexarotene may modulate numerous metabolic pathways involved in atherosclerosis. Here, we investigated the effect of bexarotene on atherosclerosis progression in a dyslipidemic murine model, the human apolipoprotein E2 knockin mouse, that develops essentially macrophage-laden lesions. Methods and Results - Atherosclerotic lesions together with different metabolic pathways involved in atherosclerosis were investigated in mice treated or not with bexarotene. Bexarotene protects from atherosclerosis development in mice, at least in part by improving the circulating cholesterol distribution profile likely via a marked decrease of dietary cholesterol absorption caused by modulation of intestinal expression of genes recently identified as major players in this process, Niemann-Pick-C1-Like1 (NPC1L1) and CD13. This atheroprotection appears despite a strong hypertriglyceridemia. Moreover, bexarotene treatment only modestly modulates inflammatory gene expression in the vascular wall, but markedly enhanced the capacity of macrophages to efflux cellular lipids. Conclusion - These data provide evidence of a favorable pharmacological effect of bexarotene on atherosclerosis despite the induction of hypertriglyceridemia, likely via a beneficial action on intestinal absorption and macrophage efflux

30th Franco-Belgian conference of Pharmacochemistry

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