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Candidate Compounds (candidate + compound)
Selected AbstractsCarisbamate, a Novel Antiepileptic Candidate Compound, Attenuates Alcohol Intake in Alcohol-Preferring RatsALCOHOLISM, Issue 8 2009Amir H. Rezvani Background:, Since 1994, when naltrexone (Revia®) was approved by the FDA for the treatment of alcoholism, only 2 other drugs (Campral® and Topamax®) have been approved for alcoholism treatment. However, various experimental drugs, including antiepileptic medications, have been tested in both animal models and in humans with some promising results. The purpose of this project was to study the effect of the novel neuromodulator carisbamate, which is in development for epilepsy treatment, on alcohol intake in selectively bred alcohol-preferring rats. Methods:, Male alcohol-preferring inbred P rats were allowed to freely drink water or alcohol (10%, v/v) using a 2-bottle choice procedure. After stable baselines for alcohol and water intakes were established, the acute effects of oral carisbamate (0, 10, 30, 45, 60, and 90 mg/kg) were assessed. Then, the chronic effect of the compound (60 mg/kg/day for 14 consecutive days) on alcohol intake was assessed in a separate group of male P rats. In another set of experiments, the effects of carisbamate and naltrexone on alcohol withdrawal-induced elevated drinking of alcohol, an index of craving, were compared. Rats were withdrawn from alcohol for 24 hours and were given vehicle, 20 mg/kg naltrexone or 60 mg/kg carisbamate 30 minutes before re-exposure to alcohol. Alcohol and water intake was measured 6 hours after alcohol re-exposure. To determine the effects of carisbamate on saccharin preference, rats were put on a 2-bottle choice of water versus a solution of 2% saccharin. Then, the effect of the highest dose of carisbamate (90 mg/kg) and naltrexone (20 mg/kg) and the vehicle on saccharin preference was determined. Results:, Our results showed that there was a selective dose-dependent reduction in alcohol intake and preference in the alcohol-preferring P rat after an acute oral administration of carisbamate. There were no significant effects on food or water intake. Chronic administration of carisbamate significantly reduced alcohol intake and preference initially, but partial tolerance developed after the 10th treatment. The degree of tolerance development was less than that observed for naltrexone. Acute administration of carisbamate was more effective than naltrexone in reducing enhanced alcohol intake after a period of alcohol deprivation. Compared with control vehicle neither carisbamate nor naltrexone had a significant effect on saccharin intake and preference. Conclusion:, The novel neuromodulator compound carisbamate has a favorable profile of effects on alcohol intake and related measures and should be considered for testing on human alcoholics. [source] Virtual Screening Leads to the Discovery of an Effective Antagonist of Lymphocyte Function-Associated Antigen-1CHEMMEDCHEM, Issue 4 2007Miyuki Shoda Abstract The binding of lymphocyte function-associated antigen-1 (LFA-1) to its ligand on endothelial cells, intercellular adhesion molecule-1 (ICAM-1), is a crucial step in the migration of leukocytes during the early stages of inflammation and is also involved in T-cell activation. In this paper, we report the identification of a series of novel antagonists of the LFA-1/ICAM-1 interaction using ligand-based virtual screening (VS), analogue design, and structure,activity relationship (SAR) analysis. Candidate compounds were evaluated in protein binding and cell adhesion assays. Experimental evaluation of only 25 candidates selected from a pool of ,2.5 million database compounds identified an initial hit that could be expanded and converted into a lead that effectively blocked the interaction between LFA-1 and ICAM-1. [source] Shift in birch leaf metabolome and carbon allocation during long-term open-field ozone exposureGLOBAL CHANGE BIOLOGY, Issue 5 2007SARI KONTUNEN-SOPPELA Abstract Current and future ozone concentrations have the potential to reduce plant growth and increase carbon demand for defence and repair processes, which may result in reduced carbon sink strength of forest trees in long-term. Still, there is limited understanding regarding the alterations in plant metabolism and variation in ozone tolerance among tree species and genotypes. Therefore, this paper aims to study changes in birch leaf metabolome due to long-term realistic ozone stress and to relate these shifts in the metabolism with growth responses. Two European white birch (Betula pendula Roth) genotypes showing different ozone sensitivity were growing under 1.4,1.7 × ambient ozone in open-field conditions in Central Finland. After seven growing seasons, the trees were analysed for changes in leaf metabolite profiling, based on 339 low molecular weight compounds (including phenolics, polar and lipophilic compounds, and pigments) and related whole-tree growth responses. Genotype caused most of the variance of metabolite concentrations, while ozone concentration was the second principal component explaining the metabolome profiling. The main ozone caused changes included increases in quercetin-phenolic compounds and compounds related to leaf cuticular wax layer, whereas several compounds related to carbohydrate metabolism and function of chloroplast membranes and pigments (such as chlorophyll-related phytol derivatives) were decreasing. Some candidate compounds such as surface wax-related squalene, 1-dotriacontanol, and dotriacontane, providing growth-related tolerance against ozone were demonstrated. This study indicated that current growth-based ozone risk assessment methods are inadequate, because they ignore ecophysiological impacts due to alterations in leaf chemistry. [source] Predictive toxicogenomics approaches reveal underlying molecular mechanisms of nongenotoxic carcinogenicityMOLECULAR CARCINOGENESIS, Issue 12 2006Alex Y. Nie Toxicogenomics technology defines toxicity gene expression signatures for early predictions and hypotheses generation for mechanistic studies, which are important approaches for evaluating toxicity of drug candidate compounds. A large gene expression database built using cDNA microarrays and liver samples treated with over one hundred paradigm compounds was mined to determine gene expression signatures for nongenotoxic carcinogens (NGTCs). Data were obtained from male rats treated for 24 h. Training/testing sets of 24 NGTCs and 28 noncarcinogens were used to select genes. A semiexhaustive, nonredundant gene selection algorithm yielded six genes (nuclear transport factor 2, NUTF2; progesterone receptor membrane component 1, Pgrmc1; liver uridine diphosphate glucuronyltransferase, phenobarbital-inducible form, UDPGTr2; metallothionein 1A, MT1A; suppressor of lin-12 homolog, Sel1h; and methionine adenosyltransferase 1, alpha, Mat1a), which identified NGTCs with 88.5% prediction accuracy estimated by cross-validation. This six genes signature set also predicted NGTCs with 84% accuracy when samples were hybridized to commercially available CodeLink oligo-based microarrays. To unveil molecular mechanisms of nongenotoxic carcinogenesis, 125 differentially expressed genes (P,<,0.01) were selected by Student's t -test. These genes appear biologically relevant, of 71 well-annotated genes from these 125 genes, 62 were overrepresented in five biochemical pathway networks (most linked to cancer), and all of these networks were linked by one gene, c - myc. Gene expression profiling at early time points accurately predicts NGTC potential of compounds, and the same data can be mined effectively for other toxicity signatures. Predictive genes confirm prior work and suggest pathways critical for early stages of carcinogenesis. © 2006 Wiley-Liss, Inc. [source] | ||||||||||