Pyrimidine-based antagonists of h-MCH-R1 derived from ATC0175: In vitro profiling and in vivo evaluation

Semple, Graeme; Tran, Thuy-Anh; Kramer, Bryan; Hsu, Debbie; Han, Sangdon; Choi, Juyi; Vallar, Pureza; Casper, Martin D.; Zou, Ning; Hauser, Erin K.; Thomsen, William J.; Whelan, Kevin; Sengupta, Dipanjan; Morgan, Michael; Sekiguchi, Yoshinori; Kanuma, Kosuke; Chaki, Shigeyuki; Grottick, Andrew J.

doi:10.1016/j.bmcl.2009.09.003

Cited by 3 publications

(2 citation statements)

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“…Multiple MCHR1 antagonists have also shown dose-dependent and sustained efficacy in chronic models of obesity (Kym et al, 2005; Souers et al, 2005a,b, 2007; Vasudevan et al, 2005a,b; Carpenter et al, 2006; Hertzog et al, 2006; Tavares et al, 2006a,b; Mendez-Andino and Wos, 2007; Mendez-Andino et al, 2007; Gehlert et al, 2009; Ito et al, 2009; Semple et al, 2009; Suzuki et al, 2009; Hadden et al, 2010; Mihalic et al, 2012; Sasmal et al, 2012a,b). At the highest dose tested in DIO mice, ranging from 10 to 100 mpk, weight loss ranged from 5% at 5 days to 33% at 238 days (Ito et al, 2009; Mihalic et al, 2012).…”

Section: Pharmacologic Studies Confirm a Role For Mch In Energy Homeomentioning

confidence: 99%

The Role of Melanin-Concentrating Hormone and Its Receptors in Energy Homeostasis

MacNeil¹

2013

Front. Endocrinol.

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Extensive studies in rodents with melanin-concentrating hormone (MCH) have demonstrated that the neuropeptide hormone is a potent orexigen. Acutely, MCH causes an increase in food intake, while chronically it leads to increased weight gain, primarily as an increase in fat mass. Multiple knockout mice models have confirmed the importance of MCH in modulating energy homeostasis. Animals lacking MCH, MCH-containing neurons, or the MCH receptor all are resistant to diet-induced obesity. These genetic and pharmacologic studies have prompted a large effort to identify potent and selective MCH receptor antagonists, initially as tool compounds to probe pharmacology in models of obesity, with an ultimate goal to identify novel anti-obesity drugs. In animal models, MCH antagonists have consistently shown efficacy in reducing food intake acutely and inhibiting body-weight gain when given chronically. Five compounds have proceeded into clinical testing. Although they were reported as well-tolerated, none has advanced to long-term efficacy and safety studies.

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Section: Pharmacologic Studies Confirm a Role For Mch In Energy Homeomentioning

confidence: 99%

The Role of Melanin-Concentrating Hormone and Its Receptors in Energy Homeostasis

MacNeil¹

2013

Front. Endocrinol.

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“…Any deviation from this pattern should therefore warrant further investigation. Figure 9.38.3 shows the pattern of food intake after administration of a compound, which chronically inhibits gastric emptying (Semple et al, 2009), characterized by an increasing effect over days. Inhibition of gastric emptying can be measured by weighing gastric contents after ingestion of fixed amounts of solid or liquid meals (Guillaume et al, 2008;Maida et al, 2008).…”

Section: Potential Confounding Factors Affecting Food Intake In Pharm...mentioning

confidence: 99%

Diet‐Induced Models of Obesity (DIO) in Rodents

et al. 2012

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Obesity results from a complex interplay between a susceptible genotype and an environment that both promotes increased caloric intake and enables sustained decreases in energy expenditure. One commonly employed approach to modeling obesity in preclinical species is the diet-induced obese (DIO) rodent. Here, theoretical and practical considerations for producing obese rodents via dietary manipulation, and for assessing drug-induced changes in food intake and body weight are described. Based on these considerations, a standardized protocol for diet-induced obesity in both mouse and rat is provided and sample data from these models are also described.

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Pharmacophore Modelling, Molecular Docking and Virtual Screening for Histamine H1 Receptor Antagonists from Traditional Chinese Medicine

Wang¹,

Ren²,

Xiang³

et al. 2013

IJBBB

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Abstract-This investigation was performed to identify histamine H1-receptor antagonists from traditional Chinese medicine through virtual screening based on pharmacophore and molecular docking. First, the pharmacophore models were generated though ten known H1 receptor antagonists. The models were validated by a test database and shown to have good performance in external validation. The best pharmacophore was employed to screen Traditional Chinese Medicine Database, which resulting in a hit list of 421 compounds. Then, the hits were subjected to molecular docking for further refinement. An empirical scoring function was used to evaluate the affinity of the compounds and the target protein.Parts of compounds with high docking scores have been reported to have the related pharmacological activity in the literatures. The findings indicated that virtual screening based on pharmacophore and molecular docking can provide a helpful tool to reveal the active ingredients from Chinese herbs. It can be used for identification of novel H1 antagonists from Traditional Chinese Medicine.Index Terms-Histamine H1-receptor, virtual screening, traditional chinese medicine, active natural ingredients identification.

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Pyrimidine-based antagonists of h-MCH-R1 derived from ATC0175: In vitro profiling and in vivo evaluation

Cited by 3 publications

References 20 publications

The Role of Melanin-Concentrating Hormone and Its Receptors in Energy Homeostasis

The Role of Melanin-Concentrating Hormone and Its Receptors in Energy Homeostasis

Diet‐Induced Models of Obesity (DIO) in Rodents

Pharmacophore Modelling, Molecular Docking and Virtual Screening for Histamine H1 Receptor Antagonists from Traditional Chinese Medicine

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