New naphthalenic ligands of melatoninergic receptors]

Twenty three naphthalenic bio-isosteres of melatonin have been synthesized. The main structural variations concerned the acylamino substituents of the side chain and the alkoxy group on the 7-position of the naphthalene. Some of these compounds show greater affinity than melatonin itself for the melatonin receptor. The results of this study provide new informations on the structure affinity relationships and on the mode of interaction at the melatonin binding site.     

Conformational analysis of tripeptide Ac-Lys-Pro-Val-NH2, COOH-terminal sequence of alpha-MSH

Alpha-melanocyte stimulating hormone (alpha-MSH) is an endogenous linear tridecapeptide which interacts with the melanocortin receptors (MC1-R to MC5-R) to mediate its biological effects. Antipyretic and anti-inflammatory activities of alpha-MSH are due to the COOH-terminal peptide sequence, Lys-Pro-Val (alpha-MSH[11-13]). This tripeptide might be useful as a therapeutic agent in the control of fever and inflammatory reactions. With this aim, a theoretical conformational study of the tripeptide has been carried out using molecular dynamics. The obtained conformational space has been classified into families according to the letter-code convention to partition the phi-psi map. The lowest energy conformations of each family were used as templates to design six models of conformationally constrained nonpeptide analogues.     

Homology modeling of MT1 and MT2 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.     

Exposure to glycol ethers in a population of French men evaluated by measurement of urinary alkoxycarboxylic acids

Objectives Glycol ethers are solvents that are present in a large number of products used commercially and domestically. During recent years, ethylene glycol ether derivatives, in particular ethylene glycol methyl ether and ethylene glycol ethyl ether, have been progressively replaced by propylene glycol ether derivatives, which are less toxic. The aim of this study was to estimate the level of exposure to glycol ethers in a sample population of French men employed by the Paris Municipality by measuring the amount of alkoxycarboxylic acid metabolites in their urine.Methods Urine samples were collected at the end of two different working weeks from 109 men, 54 of whom were judged to be occupationally exposed to glycol ether-containing products. Five alkoxyacetic acids (methoxyacetic, ethoxyacetic, n-propoxyacetic, phenoxyacetic, butoxyacetic acids) from ethylene glycol derivatives, and one alkoxypropionic acid (2-methoxypropionic) from a propylene glycol derivative, were simultaneously analysed by gas chromatography coupled to electron-capture detection.Results 2-Methoxypropionic was the most frequently found alkoxycarboxylic acid. The concentration of this metabolite reached 5.6 mmol/mol creatinine. The second most common alkoxycarboxylic acid was phenoxyacetic (up to 2.3 mmol/mol creatinine). The concentrations of the other alkoxycarboxylic acids were less than 1 mmol/mol creatinine. Although the concentration of alkoxycarboxylic acids was higher among men occupationally exposed to glycol ether-containing products than among unexposed men, the difference was significant only for butoxyacetic acid.Conclusions Our data suggest that the use and exposure levels of glycol ethers have qualitatively and quantitatively changed dramatically over recent years. Particular attention should be paid in the future to alkoxypropionic acids derived from minor isomers of propylene glycol ether derivatives.     

Preparation and pharmacological evaluation of a novel series of 2-(phenylthio)benzo[b]thiophenes as selective MT2 receptor ligands

A series of N-(2-(5-fluoro-2-(4-fluorophenylthio)benzo[b]thiophen-3-yl)ethyl)acylamides was synthesized and evaluated for binding affinity and intrinsic activity at melatonin receptors. The affinity of each compound for the melatonin receptors was determined by binding studies on cloned human MT₁ and MT₂ receptors expressed in CHO cells. Agonist and antagonist potency was measured on the [³⁵S]GTPγS binding assay for the most interesting compounds. The new derivatives 8-14 showed modest to high selectivity (between 4 and 220) for MT₂ receptors. The most selective compound, N-(2-(5-fluoro-2-(4-fluorophenylthio)benzo[b]thiophen-3-yl)ethyl)but-3-enamide (14), an MT₂ ligand with affinity for the MT₂ receptor similar to that of melatonin and a 220-fold preference over MT₁ receptors, acts as a partial agonist. In addition, N-(2-(5-fluoro-2-(4-fluorophenylthio)benzo[b]thiophen-3-yl)ethyl)propionamide (9), a nanomolar MT₂ ligand with a good selectivity ratio (MT₁/MT₂ = 51) shows antagonist activity on both melatonin receptors.     

Three-dimensional quantitative structure-activity relationships of cyclo-oxygenase-2 (COX-2) inhibitors: a comparative molecular field analysis

The three-dimensional quantitative structure-activity relationship (3D-QSAR) approach using comparative molecular field analysis (CoMFA) was applied to an extensive series of 305 varied diarylheterocyclic derivatives known as COX-2 selective inhibitors. X-ray crystal structure of COX-2 bound with SC-558, a selective COX-2 inhibitor, was used to derive the putative bioactive conformation of these inhibitors. Five statistically significant models were obtained from the randomly constituted training sets (229 compounds) and subsequently validated with the corresponding test sets (76 compounds). The best predictive model (n = 229, q(2) = 0.714, N = 8, r(2) = 0.905, s = 0.291, F = 261.545) was selected for further comparison of the CoMFA contour maps obtained for steric, electrostatic, and lipophilic fields with the enzyme structure. The high level of compatibility with the COX-2 enzyme topology shows the great accuracy of this model that can predict inhibitory activities for a wide range of compounds and offers important structural insight into designing novel antiinflammatory drugs prior to their synthesis.     

Synthesis and pharmacological evaluation of new pyrazolidine-3, 5-diones as AT(1) angiotensin II receptor antagonists

On the basis of the structure of the non-peptide receptor antagonist irbesartan, a new series of AT(1) ligands was designed. In these compounds the central imidazolone nucleus of irbesartan was replaced by a pyrazolidine-3,5-dione structure. The key intermediate N-alkylpyrazolidine-3,5-diones were synthesized according to a new and general method. The most active compounds possess a spirocyclopentane ring at position 4, a linear butyl chain at position 1, and the [2'-(5-tetrazolyl)biphenyl-4-yl]methyl or [2'-(benzoylaminosulfonyl)biphenyl-4-yl]methyl group at position 2. Affinity toward the AT(1) and AT(2) receptors was assessed by the ability of the compounds to competitively displace [(3)H]AII from its specific binding sites. The most active compounds, 28 and 48, displayed high affinity for the AT(1) receptor, good selectivity AT(1) versus AT(2), and potent in vitro antagonist activity.     

Evaluation of gastroprotective,hepatoprotective and hypotensive activities of <Emphasis Type="Italic">Ulmus campestris</Emphasis> bark extract

The present study was conducted to explore the antioxidant, antiulcer, hepatoprotective and vasodilatory effects of Ulmus campestris (Ulmaceae) ethanol bark extract at different doses, using several experimental methods. The extract was evaluated for its antioxidant activity different model systems, including hydroxyl and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals and linoleic acid. For antiulcer and gastro-protective effects, ethanol- and indometacin-induced gastric damage were used, while for hepatoprotective activity, aluminium- and D-galactose induced hepato-toxicity was examined by histopathological analysis of liver section. The hypotensive effect on the contractile activity was also evaluated on endothelium-intact and endothelium-denuded porcine ring aorta.The results of the present study revealed a potent antioxidant activity against DPPH (IC₅₀= 3.90 μg/mL) and OH^? (IC₅₀=40.13 μg/mL) radicals, lipid peroxidation (30.41±2.53%) and a significant gastro-protective effect in both ethanol- and indometacin-induced gastric ulcer (90%). The extract also demonstrated a high protection against AlCl₃-D-Galactose induced hepatotoxicity. The relaxant effect of extract was endothelium-dependant (109.73%, IC₅₀=0.002 mg/mL), without any change in eNOS phosporylation.The results of the present study indicated that U. campestris ethanol bark extract exhibited considerable antioxidant activity and protective effect against gastric ulcer and liver damage, as well as a pronounced endothelium-dependent and NO-independent relaxation in porcine coronary artery.