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Contents

Novel Approaches to the Drug Therapy of Obesity
Guest Editor: Prof. Paolo Magni

Editorial Pp. 1

Currently Available Drugs for the Treatment of Obesity: Sibutramine and Orlistat Pp. 3-10
J.-P. Chaput, S. St-Pierre and A. Tremblay
[Abstract] [Full Text Article]

Hypothalamic Neuropeptide Systems as Targets for Potential Anti-Obesity Drugs Pp. 11-19
E. Dozio, M. Ruscica, M. Motta and P. Magni
[Abstract] [Full Text Article]

Cannabinoid Receptor Antagonists and the Metabolic Syndrome: Novel Promising Therapeutical Approaches Pp. 21-30
C. Cervino, R. Pasquali and U. Pagotto
[Abstract] [Full Text Article]

Lessons from Leptin’s Molecular Biology: Potential Therapeutic Actions of Recombinant Leptin and Leptin-Related Compounds Pp. 31-38
M.L.G. Correia and W.G. Haynes
[Abstract] [Full Text Article]

Adipokines and Adipocyte Targets in the Future Management of Obesity and the Metabolic Syndrome Pp. 39-45
S. Kralisch, M. Bluher, R. Paschke, M. Stumvoll and M. Fasshauer
[Abstract] [Full Text Article]

Ghrelin and Other Gastrointestinal Peptides Involved in the Control of Food Intake Pp. 47-53
F. Tassone, F. Broglio, L. Gianotti, E. Arvat, E. Ghigo and M. Maccario
[Abstract] [Full Text Article]

General Articles

Treatment Strategies of Age-Related Memory Dysfunction by Modulation of Neuronal Plasticity Pp. 55-64
T. Blank, I. Nijholt and J. Spiess
[Abstract] [Full Text Article]

New Derivatives of BM212: A Class of Antimycobacterial Compounds Based on the Pyrrole Ring as a Scaffold Pp. 65-78
M. Biava, G.C. Porretta and F. Manetti
[Abstract] [Full Text Article]

Recent Advances in the Development of Agonists Selective for β₁–Type Thyroid Hormone Receptor Pp. 79-86
J. Malm, G.J. Grover and M. Färnegårdh
[Abstract] [Full Text Article]

Biological Fingerprinting Analysis of Traditional Chinese Medicines with Targeting ADME/Tox Property for Screening of Bioactive Compounds by Chromatographic and MS Methods Pp. 87-98
Xingye Su, Liang Kong, Xiaoyuan Lei, Lianghai Hu, Mingliang Ye and Hanfa Zou
[Abstract] [Full Text Article]

Therapeutic Prospects for the Prevention of Neurodegeneration in Huntington’s Disease and the Polyglutamine Repeat Disorders Pp. 99-100
Yoko Kimura, Wyan-Ching Mimi Lee and J. Troy Littleton
[Abstract] [Full Text Article]

Abstracts

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Editorial

Obesity is recognized as a disease of epidemic proportions worldwide; as a consequence, a strong demand is now put on the development of novel effective therapies for this condition. The current multidimensional treatment of obesity includes lifestyle changes, behavioural and surgical approaches, as well as pharmacological options. The drugs approved for the clinical treatment of obesity are, however, quite few at the moment and not always effective or well tolerated. This situation seems to evolve today, since the discovery, over the last decade, of a wide range of novel biological targets relevant to food intake and energy metabolism and to obesity has stimulated a great research effort in this field. For these reasons, several promising molecules are now under evaluation at different experimental levels by numerous public and private research centers.

This Hot Topic issue of Mini-Reviews in Medicinal Chemistry has therefore been focused on novel approaches to the drug therapy of obesity and collects six updated reviews from experts involved in the development of this field.

The first article, by Chaput et al., is a critical review of the use of two drugs, sibutramine and orlistat, currently available to the clinics. The following articles of the issue will then cover in detail the families of molecules proposed and studied to target specific biological systems involved in the development and maintenance of the state of obesity. The contribution by Dozio et al. reviews the hypothalamic neuropeptide systems involved in the control of food intake and energy metabolism, such as the neuropeptide Y and the melanocortin systems, and the agonist and antagonist molecules developed to specifically modulate these targets, acting as anti-obesity drugs. The mini-review by Cervino et al. reports the state-of-the-art of cannabinoid receptor antagonists and their promising use in the treatment of obesity and the metabolic syndrome. The molecular biology of leptin, one of the most studied adipokines, is reviewed by Correia within the perspective of the potential therapeutic actions of recombinant leptin and leptin-related compounds, whereas other adipokines and adipocyte targets, useful for the future management of obesity and the metabolic syndrome, is the area reviewed by Kralisch et al.. Ghrelin and other gastrointestinal peptides involved in the control of food intake, another important field of research in the pharmacology of obesity, is the topic covered by Tassone et al.

Obesity is known to arise from the combination of environmental and genetic factors, like many highly prevalent chronic degenerative diseases. Thus, together with lifestyle changes, a future pharmacological approach will need to combine novel safe and effective drugs, several of which are reported or envisioned in this issue, together with the study of the specific genetic/genomic pattern of each individual obese subject, in the logic of pharmacogenomics.

I would like to acknowledge Ms. Afshan Siddiq for undertaking the important tasks of correspondence and publication management.

Prof. Paolo Magni, MD-PhD
University of Milan
Milan
ITALY

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Currently Available Drugs for the Treatment of Obesity: Sibutramine and Orlistat
J.-P. Chaput, S. St-Pierre and A. Tremblay

[Full Text Article]

The currently available drugs for long-term treatment of obesity are sibutramine and orlistat. They have been shown to be able to induce significant weight loss, with important co-morbidity reduction, allowing the maintenance of reduced body weight for at least 1-2 years. Cardiostimulating and gastrointestinal adverse effects are however not negligible.

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Hypothalamic Neuropeptide Systems as Targets for Potential Anti-Obesity Drugs
E. Dozio, M. Ruscica, M. Motta and P. Magni

[Full Text Article]

Food intake and energy homeostasis are controlled by peripheral humoral signals, afferent neuronal pathways to the brain and central signals, represented, in particular, by neuropeptides. This review reports the status of development of novel compounds targeting some hypothalamic neuropeptide systems which are currently viewed as potential targets to treat obesity.

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Cannabinoid Receptor Antagonists and the Metabolic Syndrome: Novel Promising Therapeutical Approaches
C. Cervino, R. Pasquali and U. Pagotto

[Full Text Article]

Recent findings in animals and in humans have shown that cannabinoid type 1 receptor antagonists are suitable to become the most promising validated class of drugs to tackle obesity and related disorders. This mini-review will provide a concise and updated revision of the state of art on this topic.

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Lessons from Leptin’s Molecular Biology: Potential Therapeutic Actions of Recombinant Leptin and Leptin-Related Compounds
M.L.G. Correia and W.G. Haynes

[Full Text Article]

Leptin, a peptide secreted by the white adipose tissue, circulates to the central nervous system and signals the status of body energy stores, regulating feeding behavior and energy balance. As human obesity is characterized by hyper-leptinemia and leptin resistance, increasing leptin sensitivity is an attractive target for obesity treatment.

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Adipokines and Adipocyte Targets in the Future Management of Obesity and the Metabolic Syndrome
S. Kralisch, M. Bluher, R. Paschke, M. Stumvoll and M. Fasshauer

[Full Text Article]

The role of adipocytes has been recently better understood. Several adipocytokines have been identified, including leptin, a main regulator of appetite and energy expenditure, adiponectin and others, as novel insulin-sensitizers/insulin-mimetics, and some others inducing insulin resistance. Adipocytokines thus represent interesting novel drug targets in the future management of obesity.

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Ghrelin and Other Gastrointestinal Peptides Involved in the Control of Food Intake
F. Tassone, F. Broglio, L. Gianotti, E. Arvat, E. Ghigo and M. Maccario

[Full Text Article]

The increasing prevalence of obesity has triggered intense research on its pharmacotherapy. Besides central neuroendocrine pathways, many peripheral endocrino-metabolic signals have been investigated, but only few are probably of some utility in weight loss. This review reports about ghrelin and other gastrointestinal peptides involved in hunger and satiety.

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Treatment Strategies of Age-Related Memory Dysfunction by Modulation of Neuronal Plasticity
T. Blank, I. Nijholt and J. Spiess

[Full Text Article]

One of the most remarkable features of the mammalian central nervous system is its ability to store large amounts of information for periods approaching a lifetime.

However, during the aging process cognitive domains, such as long-term (declarative) memory and working memory decline in some, but by far not all individuals. It is essential to understand the physiological changes that cause memory decline and also to elucidate why preserved memory abilities vary so greatly across individuals and memory tasks.

A generally accepted hypothesis has been that long-lasting activity-dependent changes in the efficacy of synaptic transmission in the mammalian brain are considered to be of fundamental importance for the storage of information. There is now a more detailed understanding of the changes in neuronal plasticity during aging at the molecular and systems levels. This review discusses recent findings on age-related changes in neuronal plasticity, which have opened up novel sites of action for therapeutic intervention.

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New Derivatives of BM212: A Class of Antimycobacterial Compounds Based on the Pyrrole Ring as a Scaffold
M. Biava, G.C. Porretta and F. Manetti

[Full Text Article]

During our investigation in the area of antimycobacterial agents, we have identified the 1,5-(4-chlorophenyl)-2-methyl-3-(4-methylpiperazin-1-yl)methyl-1H-pyrrole (BM212) as the lead compound for a new class of antimycobacterial pyrrole derivatives with potent in vitro activity against mycobacteria and with low cytotoxicity. We have also identified the salient structural features of BM212, while structure-activity relationships (SAR) and molecular modeling studies on pyrrole compounds allowed us to design and synthesize additional analogues. Among them, seven compounds revealed a very high activity (better than that of BM212 toward mycobacteria) and a very interesting protection index, comparable to that of reference compounds, such as isoniazid, streptomycin and rifampin.

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Recent Advances in the Development of Agonists Selective for β₁–Type Thyroid Hormone Receptor
J. Malm, G.J. Grover and M. Färnegårdh

[Full Text Article]

This mini-review will provide an overview on the recent design principles and structure-activity-relationship of β-selective thyroid hormone receptor (TR) agonists. The prospects for the treatment of metabolic diseases as dyslipidemia with TRβ-selective ligands are considerable enough so as to avoid cardiovascular acceleration mediated through TRα.

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Biological Fingerprinting Analysis of Traditional Chinese Medicines with Targeting ADME/Tox Property for Screening of Bioactive Compounds by Chromatographic and MS Methods
Xingye Su, Liang Kong, Xiaoyuan Lei, Lianghai Hu, Mingliang Ye and Hanfa Zou

[Full Text Article]

Traditional Chinese medicines (TCMs) are attracting increased global attention because of their potential to provide novel therapeutic agents based on substantial historical records of efficacy in man. Many strategies have been designed for the screening and selection of bioactive compounds from these complex natural products mixtures. Biological fingerprinting analysis (BFA), based on small molecule-biomacromolecule interactions in complex systems, has been applied to screen the multiple bioactive compounds in natural products. Here we review the chromatographic and MS approaches used for BFA of natural products with targeting absorption, distribution, metabolism, elimination and toxicity (ADME/Tox) properties. Such chromatographic methods cover a wide range of applications including liposome, serum proteins, liver homogenate and DNA profiling. MS methods for the characterization of molecular interactions between natural products and target molecules by ESI and MALDI-TOF MS are also discussed.

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Therapeutic Prospects for the Prevention of Neurodegeneration in Huntington’s Disease and the Polyglutamine Repeat Disorders
Yoko Kimura, Wyan-Ching Mimi Lee and J. Troy Littleton

[Full Text Article]

Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by expansion of a polyglutamine (polyQ) tract in the huntingtin protein, resulting in intracellular aggregate formation and neurodegeneration. Biochemical pathways leading from polyQ expansion to disease pathogenesis are largely unknown. Recent approaches using genetic models systems have begun to uncover nuclear and cytoplasmic pathologies that represent potential targets for therapeutic intervention.