Development Of Anti-obesity Drugs Research Articles

Potential pancreatic lipase inhibitory activity of an endophytic Penicillium species

Pancreatic lipase (PL) is considered as one of the safest target for diet-induced anti-obesity drug development. Orlistat is the only PL inhibitor approved for anti-obesity treatment till date. In the process of exploration of new PL inhibitors, we have screened culture filtrates of 70 endophytic fungi of medicinal plants using qualitative as well as quantitative in-vitro PL assays. The qualitative assays indicated potential PL inhibition in only three isolates, namely #57 TBBALM, #33 TBBALM and #1 CSSTOT. Only ethyl acetate extracts of the culture filtrates of these isolates exhibited the PL inhibition. #57 TBBLAM ethyl acetate extract of culture filtrate exhibited potential PL inhibition with an IC50 of 3.69 µg/ml which was comparable to the positive control, i.e. Orlistat exhibiting IC50 value of 2.73 µg/ml. Further molecular phylogenetic tools and morphological studies were used to identify the isolate #57 TBBALM as Penicillium species.

Models and Strategies in the Development of Antiobesity Drugs

Obesity is a leading cause of morbidity and mortality worldwide. There is still a wide disparity between the necessity and availability of safe and effective antiobesity pharmacotherapies. Current drugs are associated with adverse effects and are limited in their efficacy. There is thus an urgent need for new antiobesity agents. Animal models are critical to the study of the biological mechanisms underpinning energy homeostasis and obesity and provide useful tools for the development of novel antiobesity agents. Our understanding of the complex neuronal and hormonal systems that regulate appetite and body weight has largely been based on studies in animals. This review describes the physiological basis of appetite, rodent models used in the development of antiobesity drugs, and potential future targets for novel antiobesity agents.

Obesity Pharmacotherapy: Current Perspectives and Future Directions

The rising tide of obesity and its related disorders is one of the most pressing health concerns worldwide, yet existing medicines to combat the problem are disappointingly limited in number and effectiveness. Recent advances in mechanistic insights into the neuroendocrine regulation of body weight have revealed an expanding list of molecular targets for novel, rationally designed antiobesity pharmaceutical agents. Antiobesity drugs act via any of four mechanisms: 1) decreasing energy intake, 2) increasing energy expenditure or modulating lipid metabolism, 3) modulating fat stores or adipocyte differentiation, and 4) mimicking caloric restriction. Various novel drug candidates and targets directed against obesity are currently being explored. A few of them are also in the later phases of clinical trials. This review discusses the development of novel antiobesity drugs based on current understanding of energy homeostasis

Extract of Kuding Tea Prevents High-Fat Diet-Induced Metabolic Disorders in C57BL/6 Mice via Liver X Receptor (LXR) β Antagonism

ObjectiveTo investigate the effects of ilex kudingcha C. J. Tseng (kuding tea), a traditional beverage in China, on the metabolic disorders in C57BL/6 mice induced by high-fat diets.DesignFor the preventive experiment, the female C57BL/6 mice were fed with a standard diet (Chow), high-fat diet (HF), and high-fat diet mixed with 0.05% ethanol extract of kuding tea (EK) for 5 weeks. For the therapeutic experiment, the C57BL/6 mice were fed high-fat diet for 3 months, and then mice were split and EK was given with oral gavages for 2 weeks at 50 mg/day/kg. Body weight and daily food intake amounts were measured. At the end of treatment, the adipocyte images were assayed with a scanning electron microscope, and the fasting blood glucose, glucose tolerance test, serum lipid profile and lipids in the livers were analyzed. A reporter gene assay system was used to test the whether EK could act on nuclear receptor transcription factors, and the gene expression analysis was performed with a quantitative PCR assay.ResultsIn the preventive treatment, EK blocked the body weight gain, reduced the size of the adipocytes, lowered serum triglyceride, cholesterol, LDL-cholesterol, fasting blood glucose levels and glucose tolerance in high-fat diet-fed C57BL/6 mice. In the therapeutic treatment, EK reduced the size of the white adipocytes, serum TG and fasting blood glucose levels in obese mice. With the reporter assay, EK inhibited LXRβ transactivity and mRNA expression of LXRβ target genes.ConclusionWe observed that EK has both preventive and therapeutic roles in metabolic disorders in mice induced with high-fat diets. The effects appear to be mediated through the antagonism of LXRβ transactivity. Our data indicate that kuding tea is a useful dietary therapy and a potential source for the development of novel anti-obesity and lipid lowering drugs.

Gut hormones: the future of obesity treatment?

Obesity is a major worldwide health problem. The treatment options are severely limited. The development of novel anti-obesity drugs is fraught with efficacy and safety issues. Consequently, several investigational anti-obesity drugs have failed to gain marketing approval in recent years. Anorectic gut hormones offer a potentially safe and viable option for the treatment of obesity. The prospective utility of gut hormones has improved drastically in recent years with the development of longer acting analogues. Additionally, specific combinations of gut hormones have been demonstrated to have additive anorectic effects. This article reviews the current stage of anti-obesity drugs in development, focusing on gut hormone-based therapies.

Cardiovascular Risk Assessment in the Development of New Drugs for Obesity

THE US FOOD AND DRUG ADMINISTRATION (FDA), CENter for Drug Evaluation and Research, convened a meeting of the Division of Metabolism and Endocrinology Products on March 28-29, 2012, to consider cardiovascular safety requirements for approval of new drugs to treat obesity. The broader context at that time involved 4 recent individual drug product reviews, resulting in no new antiobesity drugs approved and 1 drug (sibutramine) withdrawn from the market. For pharmacologic weight loss to be more than cosmetic, it is essential to demonstrate measurable health benefits. Because obesity is associated with excess cardiovascular risk and weight loss treatments could potentially mitigate that risk, it is important to assess the effect of these drugs on cardiovascular morbidity and mortality. Stimulation of sympathetic activity is the principal mechanismofactionofseveralantiobesitydrugsapprovedbytheFDA during the past 50 years. These drugs have the potential to increase blood pressure, heart rate, or both, thereby contributing directly to increased cardiovascular risk, possibly offsetting the clinical benefits of weight reduction. For example, a postmarketingcardiovascularoutcomestrial(CVOT)ofsibutramine,asympatheticagentthatinhibitsserotonin-norepinephrine reuptake,demonstratedanincreasedriskofmajoradversecardiac events (MACEs), leading to market withdrawal in 2010. This along with the previously documented adverse cardiac effects of valvulopathy and pulmonary hypertension associatedwithfenfluramine(anothersympathomimeticagent)have raised concerns about the cardiovascular safety of all new antiobesity drugs. Evaluating the cardiovascular effects of these drugs, particularly in the population with underlying cardiovascular disease, is a current regulatory focus that has broad implications for future antiobesity drug development. Weight loss of approximately 5% achieved through lifestyle modification is clinically meaningful and, accordingly, is the recommended milestone for drug development. Recent pharmacologic candidate agents have relatively modest effects on weight loss at 1 year. Mean placebosubtracted weight loss ranges from 3% for lorcaserin to 9% with phentermine/topiramate (TABLE). The degree of weight loss early in treatment may identify subpopulations likely to sustain clinically meaningful long-term weight reductions. Combination drug products appear to be associated with greater magnitude weight loss than a single agent, but at a potential expense of reduced safety and tolerability. Cardiovascular safety informationaboutnewdrugshaspreviously been limited because the premarketing trials have included relatively healthy individuals (mostly women) at low cardiovascular risk (event rates of ~0.5% annually). Consequently, theactualnumberof cardiovascular events is lowand the attribution uncertain due to lack of prospective adjudication.Forexample,thenaltrexone/bupropionpremarketingtrials accumulatedonly4MACEs(1strokewithplaceboand3myocardial infarctions with drug), phentermine/topiramate providedonly12events,andlorcaserinhadonly11events(Table). At the March 2012 meeting, the FDA advisory committee supported several strategies to assess cardiovascular risk. The principal recommendation was to rule out a prespecified unacceptable level of cardiovascular risk similar to the FDA draft guidance for new oral agents to treat type 2 diabetes. This “exclusion of excess risk” approach requires the upper bound of 95% CI of the risk difference to be no worse than what is clinically acceptable as defined by the overall benefit-risk balance of the drug: tolerating a greater degree of risk for greater weight loss and ancillary benefits in cardiometabolic profile. Excluding risk is dependent on acquiring a sufficient number of events. For example, if the population MACE rate is 0.5 events per 100 patient-years and the upper bound of the 95% CI to be excluded is a risk ratio of 2.0 (a more liberal margin than required for diabetes drugs), 87 total events would be required. Given this event rate, a CVOT would need an estimated 17 400 patient-years of exposure. However, if the study population event rate were increased to 1.5 events per 100 patient-years, the number of total patient-years of exposure would be reduced to an estimated 5800. Several strategiesweresuggested to increase theMACErate. Thesecouldincludepoolingthesafetydatabasesacrossallphase 2 and 3 randomized trials and performing a meta-analysis of all cardiovascular events with prospective adjudication by an independent,blindedclinicaleventscommittee.Enrichingstudy populations with individuals at higher risk would require enrollment of obese patients with diabetes, a prior history of cardiovasculardisease,or thosewithmultiplecardiovascular risk factors. This strategy was used for sibutramine to obtain a placebo MACE annual rate of 2.9%. One potential limitation of thisapproachisthegeneralizabilityofevaluatingsafetyinahighrisk population who may be less tolerant of potential adverse eventswhentheprimary intendeduse is in lower-riskpatients.

Limitations in anti-obesity drug development: the critical role of hunger-promoting neurons

Current anti-obesity drugs aim to reduce food intake by either curbing appetite or suppressing the craving for food. However, many of these agents have been associated with severe psychiatric and/or cardiovascular side effects, highlighting the need for alternative therapeutic strategies. Emerging knowledge on the role of the hypothalamus in enabling the central nervous system to adapt to the changing environment - by managing peripheral tissue output and by regulating higher brain functions - may facilitate the discovery of new agents that are more effective and have an acceptable benefit-risk profile. Targeting the molecular pathways that mediate the beneficial effects of calorie restriction and exercise may represent an alternative therapeutic approach for the treatment of chronic metabolic disorders such as obesity.

In vitro selection of a peptide antagonist of growth hormone secretagogue receptor using cDNA display

G protein-coupled receptors (GPCRs) are major drug targets, and their ligands are currently being explored and developed by many pharmaceutical companies and independent researchers. Class A (rhodopsin-like) GPCRs compose a predominant GPCR family; therefore, class A GPCR ligands are in demand. Growth hormone secretagogue receptor (GHS-R) is a class A GPCR that stimulates food intake by binding to its peptide ligand, ghrelin. Therefore, antagonists of GHS-R are expected to exert antiobesity function. In this article, we describe the use of cDNA display to screen for successfully and identify an antagonistic peptide of GHS-R. The antagonistic peptide inhibited the ghrelin-induced increase in intracellular Ca(2+) in vitro (IC(50)=approximately10μM) and repressed the contraction of isolated animal stomach in response to ghrelin. Furthermore, peripheral administration of the peptide inhibited the food intake of mice. This work provides new insight into the development of antiobesity drugs and describes a method for the discovery of unique peptide ligands for class A GPCRs.

Differential Expression of MicroRNAs in Adipose Tissue after Long-Term High-Fat Diet-Induced Obesity in Mice

Obesity is a major health concern worldwide which is associated with increased risk of chronic diseases such as metabolic syndrome, cardiovascular disease and cancer. The elucidation of the molecular mechanisms involved in adipogenesis and obesogenesis is of essential importance as it could lead to the identification of novel biomarkers and therapeutic targets for the development of anti-obesity drugs. MicroRNAs (miRNAs) have been shown to play regulatory roles in several biological processes. They have become a growing research field and consist of promising pharmaceutical targets in various fields such as cancer, metabolism, etc. The present study investigated the possible implication of miRNAs in adipose tissue during the development of obesity using as a model the C57BLJ6 mice fed a high-fat diet.C57BLJ6 wild type male mice were fed either a standard (SD) or a high-fat diet (HFD) for 5 months. Total RNA was prepared from white adipose tissue and was used for microRNA profiling and qPCR.Twenty-two of the most differentially expressed miRNAs, as identified by the microRNA profiling were validated using qPCR. The results of the present study confirmed previous results. The up-regulation of mmu-miR-222 and the down-regulation of mmu-miR-200b, mmu-miR-200c, mmu-miR-204, mmu-miR-30a*, mmu-miR-193, mmu-miR-378 and mmu-miR-30e* after HFD feeding has also been previously reported. On the other hand, we show for the first time the up-regulation of mmu-miR-342-3p, mmu-miR-142-3p, mmu-miR-142-5p, mmu-miR-21, mmu-miR-146a, mmu-miR-146b, mmu-miR-379 and the down-regulation of mmu-miR-122, mmu-miR-133b, mmu-miR-1, mmu-miR-30a*, mmu-miR-192 and mmu-miR-203 during the development of obesity. However, future studies are warranted in order to understand the exact role that miRNAs play in adipogenesis and obesity.

Docking, CoMFA and CoMSIA studies of a series of sulfonamides derivatives as carbonic anhydrase I inhibitors

3D-QSAR methods, CoMFA region focusing (CoMFA-RF) and CoMSIA along with docking studies carried out for investigating 32 carbonic anhydrase I inhibitors. These inhibitors have been studied for the development of antiglaucoma, antitumor, antiobesity or anticonvulsant drugs. Docking analysis by GOLD provide conformations which have been realigned in CoMFA and CoMSIA models. Training set for the CoMFA–RF and CoMSIA models using 24 docked conformations gives q2Loo values of 0.615 and 0.637 and r2nv values of 0.701 and 0.713, respectively. The results of CoMFA-RF and CoMSIA with and without docked conformations were compared. The ability of prediction and robustness of the models were evaluated by test set, cross validation (leave-one-out and leave-ten-out), bootstrapping, and progressive scrambling approaches. The all-orientation search (AOS) was used to achieve the best orientation to minimize the effect of initial orientation of the structures. The docking results confirmed CoMFA and CoMSIA contour maps.

Current models and strategies in the development of antiobesity drugs

Animal models have enabled investigation of the complex mechanisms underlying energy homeostasis and, therefore, the development of antiobesity drugs.

Uroguanylin—a new gut-derived weapon against obesity?

A recent report has identified uroguanylin as an endocrine signal that exerts a physiological role in energy homeostasis, adding another factor to the gut–brain axis. From a clinical point of view, several observations highlight the uroguanylin–guanylyl cyclase C pathway as a potential therapeutic target for the development of antiobesity drugs.

Neuropsychiatric Adverse Effects of Centrally Acting Antiobesity Drugs

Central neurochemical systems including the monoamine, opioid, and cannabinoid systems have been promising targets for antiobesity drugs that modify behavioral components of obesity. In addition to modulating eating behavior, centrally acting antiobesity drugs are also likely to alter emotional behavior and cognitive function due to the high expression of receptors for the neurochemical systems targeted by these drugs within the fronto-striatal and limbic circuitry. This paper reviewed the neuropsychiatric adverse effects of past and current antiobesity drugs, with a central mechanism of action, linking the adverse effects to their underlying neural substrates and neurochemistry. Antiobesity drugs were found to have varying neuropsychiatric adverse event profiles. Insomnia was the most common adverse effect with drugs targeting monoamine systems (sibutramine, bupropion and tesofensine). These drugs had some positive effects on mood and anxiety and may have added therapeutic benefits in obese patients with comorbid depression and anxiety symptoms. Sedation and tiredness were the most common adverse effects reported with drugs targeting the m-opioid receptors (i.e., naltrexone) and combination therapies targeting the opioid and monoamine systems (i.e., Contrave™). Cognitive impairments were most frequently associated with the antiepileptic drugs, topiramate and zonisamide, consistent with their sedative properties. Drugs targeting the cannabinoid system (rimonabant and taranabant) were consistently associated with symptoms of anxiety and depression, including reports of suicidal ideation. Similar adverse events have also been noted for the D₁/D₅ antagonist ecopipam. These findings highlight the need to assess neuropsychiatric adverse events comprehensively using sensitive and validated methods early in the clinical development of candidate antiobesity drugs with a central mechanism of action.

A New Perspective of Cannabinoid 1 Receptor Antagonists: Approaches Toward Peripheral CB1R Blockers without Crossing the Blood-Brain Barrier

Since Rimonabant was withdrawn in Europe in 2008 because of its substantial CNS risk factors including depression and anxiety, the development of anti-obesity drugs targeting CB1R in the brain has been suspended and/or terminated globally. Instead, developing peripherally restricted CB1R antagonists is actively pursued in the hope that not only could they eliminate any CNS adverse effects observed with Rimonabant, but also maintain therapeutic benefits in metabolic syndrome, including obesity, type 2 diabetes, and non-alcoholic fatty liver diseases. In this review, we summarized the most recent advances that have been made on this area, with particular emphasis on various synthetic approaches, whereby the increase in polarity, water solubility and polar surface area were centralized on, toward potential peripheral-acting CB1 antagonists.

MicroRNAs in the Regulation of Adipogenesis and Obesity

Worldwide obesity is a growing health problem, associated with increased risk of chronic disease. Understanding the molecular basis of adipogenesis and fat cell development in obesity is essential to identify new biomarkers and therapeutic targets for the development of anti-obesity drugs. microRNAs (miRNAs) appear to play regulatory roles in many biological processes associated with obesity, including adipocyte differentiation, insulin action and fat metabolism. Recent studies show miRNAs are dysregulated in obese adipose tissue. During adipogenesis miRNAs can accelerate or inhibit adipocyte differentiation and hence regulate fat cell development. In addition miRNAs may regulate adipogenic lineage commitment in multipotent stem cells and hence govern fat cell numbers. Recent findings suggest miR-519d may be associated with human obesity, but larger case-control studies are needed. Few miRNA targets have been experimentally validated in adipocytes but interestingly both miR-27 and miR-519d target PPAR family members, which are well established regulators of fat cell development. In this review recent advances in our understanding of the role of miRNAs in fat cell development and obesity are discussed. The potential of miRNA based therapeutics targeting obesity is highlighted as well as recommendations for future research which could lead to a breakthrough in the treatment of obesity.

Virtual Screening Against Obesity

The development of novel drugs against obesity is one of the top priorities of worldwide drug research. In recent years, it has been facilitated by the application of virtual screening methods. In this review, we give a short introduction into obesity-related protein targets and computer-aided drug design techniques. Furthermore, we highlight the most successful virtual screening studies, outline their results, and provide suggestions for future anti-obesity drug development.

Anti-Obesity Drugs: are They Worth It?

Future Medicinal ChemistryVol. 3, No. 3 OpinionAnti-obesity drugs: are they worth it?Mark K Huntington & Roger A ShewmakeMark K Huntington† Author for correspondenceSioux Falls Family Medicine Residency Program, Center for Family Medicine, 1115 East Twentieth Street, Sioux Falls, SD 57110, USA; Department of Family Medicine, Sanford School of Medicine at The University of South Dakota, SD, USA. Search for more papers by this authorEmail the corresponding author at mark.huntington@usd.edu & Roger A ShewmakeSioux Falls Family Medicine Residency Program, Center for Family Medicine, 1115 East Twentieth Street, Sioux Falls, SD 57110, USA; Department of Family Medicine, Sanford School of Medicine at The University of South Dakota, SD, USASearch for more papers by this authorPublished Online:29 Mar 2011https://doi.org/10.4155/fmc.11.5AboutSectionsView ArticleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit View articleKeywords: adverse effectscost–effectivenessefficacyobesityweight lossBibliography1 Rucker D, Padwal R, Li SK, Curioni C, Lau DC. Long term pharmacotherapy for obesity and overweight: updated meta- analysis. BMJ335(7631),1194–1199 (2007).Crossref, Medline, CAS, Google Scholar2 O’Meara S, Riemsma R, Shirran L, Mather L, ter Riet G. 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No evidence that popular slimming supplements facilitate weight loss, new research finds. 14th July (2010). www.sciencedaily.com/releases/2010/07/100712103445.htm (Accessed 3 December 2010).Google ScholarFiguresReferencesRelatedDetailsCited ByThe effects of medicinal herbs on gut microbiota and metabolic factors in obesity models: A systematic reviewDiabetes & Metabolic Syndrome: Clinical Research & Reviews, Vol. 16, No. 9Antiobesity Effects of Natural Products from an Epigenetic Perspective4-Aminophthalazin-1(2H)-one Derivatives as Melanin Concentrating Hormone Receptor 1 (MCH-R1) AntagonistsBulletin of the Korean Chemical Society, Vol. 34, No. 12Small molecule drug screening in Drosophila identifies the 5HT2A receptor as a feeding modulation target2 July 2013 | Scientific Reports, Vol. 3, No. 1Synthesis and SAR study of pyrrolo[3,4-b]pyridin-7(6H)-one derivatives as melanin concentrating hormone receptor 1 (MCH-R1) antagonistsBioorganic & Medicinal Chemistry Letters, Vol. 23, No. 6Lipolytic proteomics5 March 2012 | Mass Spectrometry Reviews, Vol. 31, No. 5Limitations in anti-obesity drug development: the critical role of hunger-promoting neurons3 August 2012 | Nature Reviews Drug Discovery, Vol. 11, No. 9Management of Obesity in the National Health and Nutrition Examination Survey (NHANES), 2007–2008Annals of Epidemiology, Vol. 22, No. 5 Vol. 3, No. 3 Follow us on social media for the latest updates Metrics Downloaded 618 times History Published online 29 March 2011 Published in print March 2011 Information© Future Science LtdKeywordsadverse effectscost–effectivenessefficacyobesityweight lossFinancial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download

Determination of Novel Synthetic 5HT2CAgonist KOPC20010 by Gas-Chromatography/Mass Spectrometry and its Bioavailability in Sprague-Dawley Rats

5HT2C receptor among fourteen 5-HT subtypes plays important roles in several disorders such as depression, anxiety, epilepsy, schizophrenia and sleep disorders. The purpose of the study is to investigate pharmacokinetic parameters and bioavailability of a newly synthesized selective agonist of 5-HT2C receptor, KOPC-20010 (KP10) in rats after intravenous and oral administration for the development of therapeutic anti-obesity agents. KP10 was administered orally (40 mg/kg) or intravenously (20 mg/kg), blood was collected via a catheter, and analyzed by GC/MSD. The calibration curve of KP10 in plasma and urine showed high linearity (r2>0.999). The retention times of KP10 in plasma and urine were 8.7 and 9.7 min, respectively. After oral administration of 40 mg/kg, pharmacokinetic parameters were calculated as follows; Cmax value was 1242.9±1195.5 ng/mL at 1.1±0.6 hr (Tmax). AUC0->24hr and AUC0->∞ were 8034.2±960.7 and 10464.1±681.5 ng·hr/ mL, respectively. The terminal half-life was 21.9±7.6 hr. AUC0->24hr and AUC0->∞ were 4292.4±523.0 and 6111.2±756.2 ng·hr/mL, respectively, after 20 mg/kg of intravenous administration. The terminal half-life after intravenous administration was 25.1±9.4 hr. Bioavailability of KP10 was determined to 86%. The excretion amount into the urine within 48 hr was approximately 4.7 to 6.7% of the dose administered. These data may be beneficial to the anti-obesity drug development of KP10.

Oleoyl-estrone is a precursor of an estrone-derived ponderostat signal

Oleoyl-estrone (OE) is a powerful anti-obesity compound that decreases food intake, decreases insulin resistance and circulating cholesterol. OE stimulates a severe loss of body fat by decreasing adipose tissue lipid synthesis and maintaining lipolysis. Therefore, the body economy loses lipid energy because energy expenditure is maintained. This study analyses the discrepancy between OE effects and the distribution of labelled OE in plasma. Estrone radioimmunoassay of organic solvent plasma extracts of rats treated with OE showed the massive presence of acyl-estrone, but saponification did not release estrone, but containing similar unknown compound. Analysis of label distribution in plasma after oral gavages of 3H-OE showed the presence of a more hydrophilic compound than OE or any estrogen as well as 3H 2O, formed from 3H-OE in the acidic stomach medium. OE was not attached to a specific transporter in plasma. Through serum HPLC analysis we found W, a labelled derivative more hydrophilic than OE or estrone. The results were confirmed using 14C-OE. HPLC–MS/MS studies showed that plasma OE levels were one order of magnitude lower than those of W. When liver cell cytosols from rats laden with 3H-OE were incubated with nuclei from untreated rats, the OE-derived label (i.e., Ws) was found attached to nuclear DNA. Neither estradiol nor estrone interfered with its binding. W is a fairly hydrophilic compound of low molecular weight containing the estrone nucleus, but it is not an ester because saponification or esterases do not yield estrone as OE does. It is concluded that OE acts through its conversion to W, its active form; which binds to a nuclear receptor different from that of estrogen. The estimated W serum levels are proportional to the pharmacological OE effects in vivo. We postulate W as a new type of hormone that exerts the full range of in vivo effects thus far attributed to OE. The full identification of W is anticipated to open the way for the development of new OE-like anti-obesity drugs.

Neuronal Histamine and its Receptors: Implication of the Pharmacological Treatment of Obesity

Obesity is the effect of imbalance between energy intake and expenditure and forms a fundamental basis of the metabolic syndrome. A number of substances implicated in the regulation of energy metabolism represent opportunities for anti-obesity drug development. Neuronal histamine and its receptors have been shown to regulate energy metabolism and are considered as anti-obesity targets. Several histamine receptor subtypes have been identified; of these, histamine H1 and H3 receptors (H1-R and H3-R) have been specifically recognized as mediators of energy intake and expenditure. In addition, several histamine drugs related to H1-R and H3-R, have been shown to attenuate body weight gain both in rodent and human. These results provide the reagents for histamine receptors biology and may find applications in the treatment of obesity and related metabolic disorders. In this review, the development of agonists and antagonists of histamine receptors are provided.