Structure–activity relationship studies on tetralin carboxamide growth hormone secretagogue receptor antagonists

Zhao, Hongyu; Xin, Zhili; Patel, Jyoti; Nelson, Lawrence J.; Liu, Bo; Szczepankiewicz, Bruce G.; Schaefer, Verlyn G.; Falls, Hugh D.; Kaszubska, Wiweka; Collins, Christine A.; Sham, Hing L.; Liu, Gang

doi:10.1016/j.bmcl.2005.02.026

Cited by 18 publications

(13 citation statements)

References 14 publications

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“…Another peptide, D-Lys 3 -GHRP-6, was shown to be an inverse agonist in seabream GHSR (Chan et al , 2004). Several recent studies reported a number of small molecule GHSR antagonists (Demange et al , 2007; Esler et al , 2007; Liu et al , 2004; Liu et al , 2006; Moulin et al , 2007; Moulin et al , 2008a; Moulin et al , 2008b; Rudolph et al , 2007; Serby et al , 2006; Xin et al , 2006; Xin et al , 2005; Zhao et al , 2004; Zhao et al , 2005). Some of these compounds were found to decrease food intake and body weight.…”

Section: Therapeutic Implications For Inverse Agonistsmentioning

confidence: 99%

Constitutive activation of G protein-coupled receptors and diseases: Insights into mechanisms of activation and therapeutics

Tao

2008

Pharmacology & Therapeutics

146

106

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The existence of constitutive activity for G protein-coupled receptors (GPCRs) was first described in 1980s. In 1991, the first naturally occurring constitutively active mutations in GPCRs that cause diseases were reported in rhodopsin. Since then, numerous constitutively active mutations that cause human diseases were reported in several additional receptors. More recently, loss of constitutive activity was postulated to also cause diseases. Animal models expressing some of these mutants confirmed the roles of these mutations in the pathogenesis of the diseases. Detailed functional studies of these naturally occurring mutations, combined with homology modeling using rhodopsin crystal structure as the template, lead to important insights into the mechanism of activation in the absence of crystal structure of GPCRs in active state. Search for inverse agonists on these receptors will be critical for correcting the diseases cause by activating mutations in GPCRs. Theoretically, these inverse agonists are better therapeutics than neutral antagonists in treating genetic diseases caused by constitutively activating mutations in GPCRs.

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Section: Therapeutic Implications For Inverse Agonistsmentioning

confidence: 99%

Constitutive activation of G protein-coupled receptors and diseases: Insights into mechanisms of activation and therapeutics

Tao

2008

Pharmacology & Therapeutics

146

106

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“…These substances were quinazolinone derivates [67], ligands based on tri-substituted 1,2,4-triazole structure [68,69], tetralin carboxamide [70,71] isoxazole carboxamide [72], 2,4-diaminopyrimidines [73], oxindole [74], piperazine-bisamide [75] GHSR ligands as well as R-prolinol-derivate agonists [76]. …”

Section: Gpcrs As Targets For Treatment Of Cachexia and Obesitymentioning

confidence: 99%

MC4R Dimerization in the Paraventricular Nucleus and GHSR/MC3R Heterodimerization in the Arcuate Nucleus: Is There Relevance for Body Weight Regulation?

et al. 2012

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The worldwide obesity epidemic is increasing, yet at this time, no long-acting and specific pharmaceutical therapies are available. Peripheral hormonal signals communicate metabolic status to the hypothalamus by activating their corresponding receptors in the arcuate nucleus (ARC). In this brain region, a variety of G protein-coupled receptors (GPCRs) are expressed that are potentially involved in weight regulation, but so far, the detailed function of most hypothalamic GPCRs is only partially understood. An important and underappreciated feature of GPCRs is the capacity for regulation via di- and heterodimerization. Increasing evidence implicates that heterodimerization of GPCRs results in profound functional consequences. Recently, we could demonstrate that interaction of the melanocortin 3 receptor (MC3R) and the growth hormone secretagogue receptor (GHSR)-1a results in a modulation of function in both receptors. Although the physiological role of GPCR-GPCR interaction in the hypothalamus is yet to be elucidated, this concept promises new avenues for investigation and understanding of hypothalamic functions dependent on GPCR signaling. Since GPCRs are important targets for drugs to combat many diseases, identification of heterodimers may be a prerequisite for highly specific drugs. Therefore, a detailed understanding of the mechanisms and their involvement in weight regulation is necessary. Fundamental to this understanding is the interplay of GPCR-GPCR in the hypothalamic nuclei in energy metabolism. In this review, we summarize the current knowledge on melanocortin receptors and GHSR-1a in hypothalamic weight regulation, especially as they pertain to possible drug targets. Furthermore, we include available evidence for the participation and significance of GPCR dimerization.

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“…Efforts to quartenarise the amide α‐carbon to gain stability toward hydrolysis led to the carbamate 25 with improved binding affinity, antagonist potency (Scheme , IC 50 , respectively, of 16 and 29 nM) and reasonable rat bioavailability (19%). In this series, as for isoxazole carboxamides, further modification or replacement of N , N ‐diethylaniline motif did not show any improvement in potency159.…”

Section: Ghrelin Analogues and Their Biological Activitymentioning

confidence: 64%

Ghrelin—a novel generation of anti‐obesity drug: design, pharmacomodulation and biological activity of ghrelin analogues

Chollet

Meyer

Beck‐Sickinger

2009

Journal of Peptide Science

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Ghrelin is a unique bioactive peptide with respect to both the structure and its biological function. This 28-amino acid peptide is modified with an n-octanoyl group at serine-3, and accordingly is the only lipidated biologically active peptide hormone known so far. Ghrelin binds to the so-called ghrelin or GHS receptor, a member of the class A of G-protein coupled receptors, which leads to Ca(2+) release intracellularly due to the activation of the Gq-system. Interestingly, the ghrelin receptor shows a significant constitutive activity which means that in addition to agonists and antagonists, inverse agonists play an important role in receptor modulation. In this review, the major activities of ghrelin are summarized with a strong focus on the regulation of food intake. So far reported agonists, antagonists and inverse agonists are shown and structure activitiy relationships are discussed. Furthermore, the application of ghrelin ligands as novel anti-obesity drugs is outlined and the state of the art in this field is summarized.

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Structure–activity relationship studies on tetralin carboxamide growth hormone secretagogue receptor antagonists

Cited by 18 publications

References 14 publications

Constitutive activation of G protein-coupled receptors and diseases: Insights into mechanisms of activation and therapeutics

Constitutive activation of G protein-coupled receptors and diseases: Insights into mechanisms of activation and therapeutics

MC4R Dimerization in the Paraventricular Nucleus and GHSR/MC3R Heterodimerization in the Arcuate Nucleus: Is There Relevance for Body Weight Regulation?

Ghrelin—a novel generation of anti‐obesity drug: design, pharmacomodulation and biological activity of ghrelin analogues

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