Showing papers on "Growth hormone secretagogue published in 2004"

Expression of ghrelin and biological activity of specific receptors for ghrelin and des-acyl ghrelin in human prostate neoplasms and related cell lines.

Abstract: Background: Ghrelin, a natural growth hormone secretagogue (GHS), has been identified in prostate carcinoma cell lines. Objectives: To investigate the presence of ghrelin and its receptors in human prostate tumours and in DU-145, PC-3 and LNCaP prostate carcinoma cell lines, and to assesss the effects of ghrelin and its more abundant circulating form, des-octanoyl ghrelin, on cell proliferation. Methods: Ghrelin and types 1a and 1b GHS receptor (GHS-R) were determined at the mRNA and protein levels by RT-PCR, in situ hybridization, immunohistochemistry and enzyme immunoassay in tissues, cell lines and culture medium. Ghrelin binding was determined by radioreceptor assay. The effects on cell proliferation were evaluated by growth curves. Results: Ghrelin mRNA was found in prostatic carcinomas and benign hyperplasias, but immunohistochemistry was negative. GHS-R1a and 1b mRNAs were absent from carcinomas, but GHSR1b mRNA was present in 50% of hyperplasias. Ghrelin peptide and mRNA were present in PC-3 cells exclusively, whereas GHS-R1a and 1b mRNAs were expressed in DU-145 cells only. Specific [ 125 I]Tyr 4 -ghrelin binding was detected in prostate tumour, DU-145 and PC-3 cell membranes and the binding was displaced by ghrelin, synthetic GHS and des-octanoyl ghrelin, which is devoid of GHS-R1a binding affinity and GH-releasing activity. Ghrelin and des-acyl ghrelin inhibited DU-145 cell proliferation, displayed a biphasic effect in PC-3 cells and were ineffective in LNCaP cells. Conclusions: Specific GHS binding sites, other than GHS-R1a and 1b, are present in human prostatic neoplasms. Ghrelin, in addition to des-acyl ghrelin, exerts different effects on cell proliferation in prostate carcinoma cell lines.

Inhibition of ghrelin action in vitro and in vivo by an RNA-Spiegelmer

Abstract: Employing in vitro selection techniques, we have generated biostable RNA-based compounds, so-called Spiegelmers, that specifically bind n-octanoyl ghrelin, the recently discovered endogenous ligand for the type 1a growth hormone secretagogue (GHS) receptor. Ghrelin is a potent stimulant of growth hormone release, food intake, and adiposity. We demonstrate that our lead compound, L-NOX-B11, binds ghrelin with low-nanomolar affinity and inhibits ghrelin-mediated GHS-receptor activation in cell culture with an IC(50) of 5 nM. l-NOX-B11 is highly specific for the bioactive, n-octanoylated form of ghrelin. Like the GHS receptor, it does not recognize the inactive unmodified peptide and requires only the N-terminal five amino acids for the interaction. The i.v. administration of polyethylene glycol modified l-NOX-B11 efficiently suppresses ghrelin-induced growth hormone release in rats. These results demonstrate that the neutralization of circulating bioactive ghrelin leads to inhibition of ghrelin's secretory effects in the CNS.

Ghrelin Expression and Actions: A Novel Peptide for an Old Cell Type of the Diffuse Endocrine System

Abstract: Ghrelin is a gastric peptide involved in food intake control and growth hormone release. Its cell localization has been defined in distinct ghrelin cells of the gastric mucosa in humans and other mammals. Ghrelin production was also described in a number of other sites of the diffuse endocrine system, including the pituitary, thyroid, lung, pancreas, adrenal gland, and intestine. In addition, ghrelin cells were identified early during fetal life and in the placenta and gonads. Finally, endocrine growths and tumors of the diffuse endocrine system may present ghrelin-producing cells, and in a few cases high levels of circulating ghrelin were reported. Besides its well-defined orexigenic role, ghrelin is likely to exert a local paracrine role similar to other brain-gut axis hormones. This review aims to summarize recent data on ghrelin cell distribution in the diffuse endocrine system and discuss local and general ghrelin function during development, adulthood, and endocrine tumor development.

Chronic changes in peripheral growth hormone levels do not affect ghrelin stomach mRNA expression and serum ghrelin levels in three transgenic mouse models.

Abstract: Ghrelin is an endogenous ligand for the growth hormone secretagogue (GHS) receptor. Ghrelin is involved in feeding behaviour and is a potent stimulator of GH release. Chronically increased GH concentrations are known to negatively regulate the pituitary GHS receptor. This study tested whether chronic changes in peripheral GH levels/action affect ghrelin mRNA expression and circulating concentrations of ghrelin. Stomach ghrelin mRNA expression and serum concentrations of ghrelin were measured in three groups of transgenic mice and the respective control animals: group 1, GH-receptor gene disrupted mice (GHR/KO); group 2, mice expressing bovine GH (bGH); and group 3, mice expressing GH-antagonist (GHA). Ghrelin mRNA expression in the stomach, pituitary and hypothalamus of young adult male rats were measured using reverse-transcription-polymerase chain reaction. Ghrelin mRNA expression levels were approximately 3000-fold higher in rat stomach than in rat pituitary. Ghrelin mRNA expression in rat hypothalamus was below the detection limits of our assay. Stomach ghrelin mRNA expression, as well as serum concentrations of ghrelin, did not change significantly in any of the three mouse groups compared to the respective control group. These data support previous observations that the stomach is the main source of circulating ghrelin, and also indicate that stomach ghrelin mRNA expression and serum concentrations of ghrelin are not affected by chronic changes in peripheral GH/insulin-like growth factor-I levels/action.

Growth hormone secretagogue receptor subtypes 1a and 1b are expressed in the human adrenal cortex.

Abstract: Ghrelin is an endogenous ligand of the growth hormone secretagogue receptors (GHS-Rs), two subtypes of which have been recognized: the biologically active 1a and the biologically inactive 1b subtype. Reverse transcription-polymerase chain reaction demonstrated ghrelin and GHS-R1b mRNAs in eight human adrenal cortexes, and GHS-R1a mRNA only in six of the eight adrenal specimens. The GHS-R1a expression was absent in the two adrenal cortexes obtained from 76- and 79-year old male patients. Since previous studies showed that ghrelin does not affect steroid-hormone secretion, the present findings suggest that ghrelin via the GHS-R1a could be involved in the autocrine-paracrine control of human-adrenal growth.

Identification of Structurally Diverse Growth Hormone Secretagogue Agonists by Virtual Screening and Structure−Activity Relationship Analysis of 2-Formylaminoacetamide Derivatives

Abstract: Two molecules with known growth hormone secretagogue (GHS) agonist activity were used as templates to computationally screen ∼80000 compounds. A total of 108 candidate compounds were selected, and five of them were found to be active in the low-micromolar range in both cell-based and direct binding assays. These compounds were structurally diverse and significantly differed from known GHS agonists. The most active compound was subjected to SAR evaluation, which slightly increased its potency and identified molecular regions important for specific GHS agonist activity.

Pharmaceutical compositions and methods comprising combinations of 2-alkylidene-19-nor-vitamin d derivatives and a growth hormone secretagogue

Abstract: The present invention relates to pharmaceutical compositions and methods of treatment comprising administering to a patient in need thereof a combination of a 2-alkylidene-19-nor-vitamin D derivative and a growth hormone secretagogue or a pharmaceutically acceptable salt or prodrug thereof. Particularly, the present invention relates to pharmaceutical compositions and methods of treatment comprising administering to a patient in need thereof 2-methylene-19-nor-20(S)-1α,25-dihydroxyvitamin D3 and a growth hormone secretagogue or a pharmaceutically acceptable salt or prodrug thereof. I

Growth hormone secretagogue receptor agonists

Abstract: The present invention relates to growth hormone secretagogue (GHS) receptor agonists. In particular, the present invention relates to novel therapeutic uses of GHS receptor agonists. The novel applications of GHS receptor agonists relate to thermic control of body temperature which has proven to be beneficial in a number of pathologic conditions.

Combination of gh secretagogues and pde4 inhibitors for the treatment of alzheimer's disease

Abstract: There is disclosed the treatment or prevention of diseases involving deposition of beta-amyloid in the brain, e.g. Alzheimer's disease, via the combined administration of a growth hormone secretagogue and a PDE4 inhibitor.

Known and Unknown Growth Hormone Secretagogue Receptors and their Ligands

Abstract: The discovery of ghrelin is a typical example of reverse pharmacology: first the synthetic analogues (i.e. peptidyl and non-peptidyl growth hormone secretagogues (GHS)); second the receptor; third the natural ligand for this orphan receptor, i.e. ghrelin. Ghrelin is providing new understanding about how the gastrointestinal tract and nutritional intake regulate appetite, food intake and energy expenditure as well as the function of hypothalamus-pituitary axis, particularly the somatotroph function. However, ghrelin and its synthetic analogues also exert other peripheral, endocrine and nonendocrine actions including influence on the endocrine pancreas and glucose metabolism, on gastroenteropancreatic and cardiovascular functions, as well as modulation of cell proliferation. The classical ghrelin receptor, i.e., the GHS receptor type la (GHS-R1a) is widely distributed and mediates many of the biological actions of ghrelin and synthetic GHS. GHS-R type 1b a splice variant of the GHS-R1a, is even more widely distributed in central and peripheral tissues but its function is still unknown. Other GHS-R subtypes, i.e., other ghrelin receptors are likely to exist. In fact, GHS-R1a is bound by acylated ghrelin only but the existence of a receptor able to bind ghrelin independently of its acylation has been already demonstrated in agreement with evidence that unacylated ghrelin, although devoid of endocrine actions, possesses cardiovascular effects and modulates cell proliferation. Moreover, the existence of specific receptors mediating some cardiovascular actions of peptidyl GHS only and that do not recognize ghrelin has been demonstrated. Whether ghrelin is the sole ligand or one of a number of ligands activating the GHS-R1a is, at present, under investigation; on the other hand, it has also to be clarified whether the GHS-R used for ghrelin isolation is the sole receptor or one of a group of receptors for one or more than one ligand.

Enhancement of growth hormone levels with a dipeptidyl peptidase iv inhibitor and a growth hormone secretagogue

Abstract: The present invention is directed to methods for increasing levels of endogenous growth hormone in a mammal by the administration of a combination of a dipeptidyl peptidase IV (DP-IV) inhibitor and a growth hormone secretagogue.

Discovery of Ghrelin, an Endogenous Ligand for the Growth-Hormone Secret Agogue Receptor

Abstract: Small synthetic molecules called growth-hormone secretagogues (GHS) stimulate the release of growth hormone (GH) from the pituitary. They act through the GHS-receptor (GHS-R), a G-protein-coupled receptor. We purified and identified the endogenous ligand for the GHS-R and named it “ghrelin,” after a word root (“ghre”) in Proto-Indo-European languages meaning “grow”. Ghrelin is a peptide hormone in which the third amino acid, usually a serine but in some species a threonine, is modified by a fatty acid; this modification is essential for ghrelin’s activity. Ghrelin is an essential hormone for maintaining GH release and energy homeostasis in vertebrates.

Use of growth hormone secretagogues for treatment of fibromyalgia

Abstract: This invention is directed to a method of treating fibromyalgia in a patient which comprises administering a growth hormone secretagogue, prodrugs thereof or pharmaceutically acceptable salts of said secretagogues or said prodrugs to a patient in need thereof. The present invention provides such a method wherein the growth hormone secretagogue is a compound of Formula I: a prodrug thereof or a pharmaceutically acceptable salt of said secretagogue or said prodrug and wherein the variables HET, R3, R4, X4, R6, R7 and R8 are as defined in the specification.

Fluorescently labeled growth hormone secretagogue

Abstract: The present invention relates to a fluorescently labeled growth hormone secretagogue which can be used for the identification of compounds capable of binding to growth hormone secretagogue receptors, in particular by high throughput screening.

[Ghrelin: a new peptide regulating the neurohormonal system and energy homeostasis].

Abstract: Ghrelin: a new peptide regulating the neurohormonal system and energy homeostasis. Research leading to the identification of ghrelin started with the discovery of growth hormone secretagogues, continued with the description of ghrelin receptors and ended with description of the chemical structure of ghrelin. However, several aspects concerning the role of ghrelin in physiology and pathophysiology are still under investigation. The majority of ghrelin is produced in the stomach, but it is also expressed in the hypothalamus, pituitary, intestine, kidney, heart, pancreas and gonads. Ghrelin stimulates growth hormone secretion via growth hormone secretagogue receptors, and it increases appetite. Ghrelin secretion in the stomach depends on both acute and chronic changes in energy balance. Presently available data support the hypothesis that the stomach, in addition to its important role in digestion, not only influences pituitary hormone secretion via ghrelin production but it also sends orexigenic (appetite increasing) signals to hypothalamic nuclei involved in the regulation of energy homeostasis. In addition to these main effects, ghrelin influences the cardiovascular, gastrointestinal, reproductive and endocrine functions. It can be anticipated that further research on the physiological and pathophysiological role of ghrelin will lead to a better understanding of neurohormonal processes and the central regulation of energy homeostasis.

Fluorescently labelled Ghrelin peptides.

Abstract: The present invention relates to a fluorescently labeled growth hormone secretagogue which can be used for the identification of compounds capable of binding to growth hormone secretagogue receptors, in particular by high throughput screening: R1-Cys-F wherein R1 is a ghrelin peptide, and F is a fluorochrome.

Treatment for alzheimer's disease and related conditions

Abstract: This invention provides the combination of a growth hormone secretagogue and a p38 kinase inhibitor for use in treatment or prevention of a disease associated with deposition of Aβ in the brain.

Tritiated growth hormone secretagogue mk-0677

Abstract: The present invention relates to a tritiated growth hormone secretagogue which can be used for the identification of compounds capable of binding to growth hormone secretagogue receptors, or of compounds having activity as growth hormone secretagogues.

Ghrelin: Central Actions and Potential Implications in Neurodegenerative Diseases

Abstract: The growth hormone releasing peptides (GHRP) and their peptidomimetics were the first synthetic compounds known that stimulated both growth hormone (GH) release and appetite. Subsequently, a new orphan receptor, the growth hormone secretagogue (GHS-R), was cloned that mediated the action of these compounds. Following cloning of the GHS-R, cell lines engineered to express the cloned GHS-R provided the assays that were essential for identification of ghrelin as an endogenous GHS-R ligand in stomach tissue extracts. Ghrelin was recently also shown to be produced by a discrete network of neurons in the hypothalamus that control appetite, which are distinct from the network that regulates GH pulsatility. We describe how studies with ghrelin and its mimetics helped elucidate the mechanisms by which ghrelin regulates these distinct pathways. Localization of GHS-R expression in the brain suggests that ghrelin also modulates the function of neurons involved in memory, learning, cognition, mood and sleep. Indeed, results from studies with GHS-R (ghrelin-receptor) knockout mice indicate that reduced expression of the GHS-R causes deficits in contextual memory. This has implications for age-related neurodegeneration because ghrelin production declines in elderly adults and aging is associated with a decline in amplitude of GH-pulsatility, altered appetite, changes in metabolism and deficiencies in contextual memory. Ghrelin has the potential to prevent/reverse these changes; therefore, perhaps ghrelin is important for maintaining a young adult phenotype and providing protection against neurodegenerative diseases.