Mini Reviews in Medicinal Chemistry - Volume 7, Issue 8, 2007

Research into the endocannabinoid signaling system has grown exponentially in recent years following the discovery of cannabinoid receptors (CB) and their endogenous ligands, such as anandamide (AEA) and 2- arachidonoylglycerol (2-AG). Important advances have been made in our understanding of the endocannabinoid signaling system in various aspects of alcoholism, including alcohol-seeking behavior. Alcohol increases the synthesis or impairs the degradation of endocannabinoids, leading to a locally elevated endocannabinoid tone within the brain. Elevated endocannabinoid tone might be expected to result in compensatory down-regulation of CB1 receptors or dampened signal transduction. Following release, endocannabinoids diffuse back to the presynaptic neuron where they act as short-range modulators of synaptic activity by altering neurotransmitter release and synaptic plasticity. Mice treated with the CB1 receptor antagonist SR141716A (rimonabant) or homozygous for a deletion of the CB1 receptor gene exhibit reduced voluntary alcohol intake. CB1 knockout mice also show increased alcohol sensitivity, withdrawal, and reduced conditioned place preference. Conversely, activation of CB1 receptor promotes alcohol intake. Recent studies also suggest that elevated endocannabinoid tone due to impaired degradation contributes to high alcohol preference and self-administration. These effects are reversed by local administration of rimonabant, suggesting the participation of the endocannabinoid signaling system in high alcohol preference and self-administration. These recent advances will be reviewed with an emphasis on the endocannabinoid signaling system for possible therapeutic interventions of alcoholism.

Accumulating evidence indicates that cancer is maintained by cancer stem cells (CSC). The goal of molecular imaging is to detect pathologic biomarkers, which can lead to early recognition of cancer, better therapeutic management, and improved monitoring for recurrence. The main focus of this review is to describe the different classes of tracers, contrast agents and dyers, and their putative application to improve cancer stem cells detection and follow-up. Although the in vivo cancer diagnosis has not significantly changed for the past three decades, however, in the future it might be possible to trace all cancer cells, including the cancer stem cells.

The aim of this review is precisely to give a comprehensive account of the large volume of work carried out on 1,4-diazepines regardless of the degree of unsaturation in the diazepine system. This review mainly emphasizes recent work on the diazepines also including earlier work.

We describe synthesis of α-methylated analogues of the natural polyamines and their use as tools in unraveling polyamine functions. Experiments with α-methylated spermidine and spermine revealed that the polyamines are exchangeable in supporting cellular growth. Degradation of the analogues by polyamine oxidase disclosed hidden, aldehydeguided stereospecificity of the enzyme.

Histamine is a neurotransmitter and neuromodulator within the central nervous system that affects the regulation of food intake and obesity. This review focuses on the roles of neuronal histamine and its receptors in regulating food intake and obesity.

There has been a renewed interest to the application of natural products derived from cruciferous plants and members of Allium genus in chemoprevention of cancer. The potential chemopreventive properties of these vegetables have been attributed to the presence of high level of organosulfur compounds in these plants. Organosulfur compounds have been shown to exert diverse biological effects such as: (a) induction of carcinogen detoxification, (b) inhibition of tumor cell proliferation, (c) antimicrobial effect, (d) free radical scavenging, (e) inhibition of DNA adduct formation, (f) induction of cell cycle arrest and induction of apoptosis etc. It has been suggested that these compounds act as chemopreventive agents through a combination of above mechanisms. Epidemiological and experimental carcinogenesis provides overwhelming evidence to support the claim that individuals consuming diet rich in organosulfur are less susceptible to different types of cancers. The protective effects of OSCs against carcinogenesis have been shown in stomach, esophagus, mammary glands, breast, skin and lungs of experimental animals. Cumulatively all these studies show a strong correlation between cancer prevention and intake of organosulfur compounds in one form or the other. Since the protective effects of all these phytochemicals are as a result of additives and synergistic combination further studies are warranted for complete understanding of chemopreventive action of organosulfur compounds and define the effective dose that has no toxicity in humans. In this review an attempt has been made to summarize the different aspects of organosulfur compounds with relation to their source, chemopreventive mechanistic action, epidemiologic and experimental carcinogenesis.

Acute infection due to hepatitis C virus results in a chronic progression in 50-84% of cases. In the light of the risk of developing chronic disease and the response rate to treatment once the disease is established, it is very important to consider early treatment of acute hepatitis C before it progresses to the chronic form. The aim of this review is to evaluate the real efficacy and tolerance of Peg-interferon alfa-2b in monotherapy and in association with ribavirin in the treatment of patients affected by acute C hepatitis, to delineate the viral factors correlated with the sustained virological response and to consider when treatment should be started in relation to onset and what is the optimal duration of therapy. Also the pharmacodynamic and pharmacokinetic characteristics of PEG-IFN alfa-2b and ribavirin are reassessed. The analysis of literature demonstrates that Peg-interferon alfa-2b treatment is efficacious in terms of attaining sustained virological response (71-94% of cases). Treatment must be started within three months of onset and must be prolonged for three months. Only two studies have provided evidence the needed of a prolonged treatment for six months for genotype 1 infections. In all studies therapy has been generally well tolerated. Sustained virological response is independent of baseline viral load and of HCV genotypes in patients treated for six months, while in subjects treated for three months it seems to be dependent on HCV-genotype, with genotype 1 characterized by a less favourable outcome. Combination therapy with ribavirin does not seem to increase the response rate but could be proposed as a second choice to patients not responding to IFN monotherapy.

FTY720, the pharmacological analog of S1P, acts as an agonist of sphingosine-1-phosphate receptors, resulting in the inhibition of lymphocyte egress from secondary lymphoid tissues and thymocytes from the thymus, peripheral lymphopenia and interfering with normal functions of several other cell types. FTY720 has been clinically tried for transplantation and multiple sclerosis, showing promising protective effects. This review will summarize potential applications and effects of FTY720.

Large libraries of chemical compounds reflect the exponentially growing data-enrichment in drug discovery that trends towards fully automated informatics solutions to study structure - activity relationships by screening docked ligand candidates to biological target structures. We review otherwise disseminated user descriptions of mainly public databases with free access and also our integrated data mining tool GPDBnet for phyto-pharmacology.

The main function of the innate immune system from insects to mammals is to detect the presence of and act against invading microorganisms by recognizing their unique molecular signatures, most importantly, components of bacterial cell walls. A large number of peptides and derivatives, both synthetic and of natural origin, are known to influence immune responses in mammals by interacting with the conserved microbial structures, making the former attractive targets for drug development. This review focuses on structural aspects of the immunomodulating peptides and their receptors, including primary constitution, stereochemistry, conformation, binding and hydrophobic properties.

Ovarian hormone deficiency status is associated with increased cardiovascular morbidity and mortality, suggesting that estrogen might exhibit a favorable cardiovascular effect. Estrogen has a multitude of beneficial biological effects on surrogate markers of cardiovascular disease that may account for this hypothesis. However, none of the randomized trials already conducted with hormone replacement therapy showed overall benefit by means of reducing clinical ischemic cardiovascular events and/or suppressing atherogenesis. Moreover, the Women's Health Initiative study (WHI) has suggested a possible detrimental effect for hormone replacement therapy including increased cardiovascular morbidity, ovarian and breast cancer. Hence, any beneficial effect of estrogen must be carefully weighed against its carcinogenic properties together with its side effects. The need for a more efficient and specific molecule led to the development of the selective estrogen receptor modulators (SERMs). This new generation of drugs mimick the effect of estrogen in some tissues while antagonize several estrogen effects in other tissues. These unique properties offer the possibility to attain the beneficial effects of estrogen while avoiding its carcinogenic effect and the accompanying adverse reactions. Here we review the different effects of raloxifene- a protype second generation SERM on the cardiovascular system. We discuss raloxifene's role at different levels of the atherothrombotic cascade addressing each level separately; trying to clarify the net effect of raloxifene in modulating thrombosis in the arterial tree.