Discovery of a new class of ghrelin receptor antagonists

Mihalic, Jeffrey T.; Kim, Yong-Jae; Lizarzaburu, Mike E.; Chen, Xiaoqi; Deignan, Jeff; Wanska, Malgorzata; Yu, Ming; Fu, Jiasheng; Chen, Xi; Zhang, Alex; Connors, Richard; Liang, Lingming; Lindström, Michelle; Ma, Ji; Tang, Liang; Dai, Kang; Li, Leping

doi:10.1016/j.bmcl.2012.01.014

Cited by 22 publications

(22 citation statements)

References 12 publications

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“…3) (28). Using an aequorin mitochondrial-based assay, we measured bioluminescence differences reflecting G q/11 mediated Ca 2ϩ mobilization between the wild type and the chimeric receptors in HEK293 cells (29,32). Interestingly, L585 was more potent than ghrelin in stimulating Ca 2ϩ , with EC 50 values of 2.7 Ϯ 1.2 nM and 93.5 Ϯ 11.6 nM, respectively (Fig.…”

Section: Erk1/2 Phosphorylationmentioning

confidence: 97%

“…Ca 2ϩ mobilization was determined using a functional bioluminescence-based aequorin (Aeq) assay (29,32). HEK293 cells permanently expressing 3xHA-GHSR1a and mitochondrial apoaequorin were trypsinized, spun down, and resuspended in 1.5 ml of assay medium which contained DMEM, 10% FBS, 10 mM HEPES, and 2.5 M coelenterazine-h (Promega, Madison, WI).…”

Section: ؉ Mobilization Assaysmentioning

confidence: 99%

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G Protein and β-Arrestin Signaling Bias at the Ghrelin Receptor

Evron

Peterson

Urs

et al. 2014

Journal of Biological Chemistry

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Background:The G protein coupled receptor GHSR1a mediates feeding and addictive behaviors. Results: Mutagenesis of the second intracellular loop of GHSR1a generates biased receptors, favoring distinct signaling events. Conclusion: Receptor conformations that support signaling bias at the wild-type receptor should exist. Significance: Recapitulating signaling bias at GHSR1a may facilitate the identification of novel selective therapies to treat addiction.

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Section: Erk1/2 Phosphorylationmentioning

confidence: 97%

Section: ؉ Mobilization Assaysmentioning

confidence: 99%

G Protein and β-Arrestin Signaling Bias at the Ghrelin Receptor

Evron

Peterson

Urs

et al. 2014

Journal of Biological Chemistry

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“…170 A HTS of the Amgen compound deck led to 15a (Figure 8) which was shown in an aequorin functional assay to be a full antagonist. Compound 15a was metabolically labile; thus, the authors set out to improve metabolic stability in this chemical space.…”

Section: ■ Amgenmentioning

confidence: 99%

Small Molecule Ghrelin Receptor Inverse Agonists and Antagonists

2014

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Ghrelin is an endogenous peptide hormone secreted primarily by the stomach and is involved in a number of physiological processes including growth hormone secretion, food intake, as well as energy and glucose homeostasis. The physiological actions of ghrelin are mediated through the growth hormone secretagogue receptor 1a (ghrelin receptor), a peptidic G-protein-coupled receptor. This target has attracted much interest, as agents that block ghrelin's actions on its receptor are anticipated to be pharmaceutical interventions for a number of diseases. This review provides an overview of ghrelin biology with a focus on metabolic diseases and summarizes recent medicinal chemistry programs aimed at delivering small molecule ghrelin receptor antagonists and inverse agonists to the clinic.

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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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Discovery of a new class of ghrelin receptor antagonists

Cited by 22 publications

References 12 publications

G Protein and β-Arrestin Signaling Bias at the Ghrelin Receptor

G Protein and β-Arrestin Signaling Bias at the Ghrelin Receptor

Small Molecule Ghrelin Receptor Inverse Agonists and Antagonists

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

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