[Show abstract][Hide abstract]ABSTRACT: The present invention provides novel triazole derivatives as ghrelin analogue ligands of growth hormone secretagogue receptors according to formula (I) that are useful in the treatment or prophylaxis of physiological and/or pathophysiological conditions in mammals, preferably humans, that are mediated by GHS receptors. The present invention further provides GHS receptor antagonists and agonists that can be used for modulation of these receptors and are useful for treating above conditions, in particular growth retardation, cachexia, short-, medium- and/or long term regulation of energy balance; short-, medium- and/or long term regulation (stimulation and/or inhibition) of food intake; adipogenesis, adiposity and/or obesity; body weight gain and/or reduction; diabetes, diabetes type I, diabetes type II, tumor cell proliferation; inflammation, inflammatory effects, gastric postoperative ileus, postoperative ileus and/or gastrectomy (ghrelin replacement therapy).
[Show abstract][Hide abstract]ABSTRACT: We investigated whether ghrelin action at the level of the ventral tegmental area (VTA), a key node in the mesolimbic reward system, is important for the rewarding and motivational aspects of the consumption of rewarding/palatable food. Mice with a disrupted gene encoding the ghrelin receptor (GHS-R1A) and rats treated peripherally with a GHS-R1A antagonist both show suppressed intake of rewarding food in a free choice (chow/rewarding food) paradigm. Moreover, accumbal dopamine release induced by rewarding food was absent in GHS-R1A knockout mice. Acute bilateral intra-VTA administration of ghrelin increased 1-hour consumption of rewarding food but not standard chow. In comparison with sham rats, VTA-lesioned rats had normal intracerebroventricular ghrelin-induced chow intake, although both intake of and time spent exploring rewarding food was decreased. Finally, the ability of rewarding food to condition a place preference was suppressed by the GHS-R1A antagonist in rats. Our data support the hypothesis that central ghrelin signaling at the level of the VTA is important for the incentive value of rewarding food.
[Show abstract][Hide abstract]ABSTRACT: In the present study, we explore the central nervous system mechanism underlying the chronic central effects of ghrelin with respect to increasing body weight and body fat. Specifically, using a recently developed ghrelin receptor antagonist, GHS-R1A (JMV2959), we investigate the role of GHS-R1A in mediating the effects of ghrelin on energy balance and on hypothalamic gene expression. As expected, in adult male rats, chronic central treatment with ghrelin for 14 days, when compared to vehicle-treated control rats, resulted in an increased body weight, lean mass and fat mass (assessed by dual X-ray absorptiometry), dissected white fat pad weight, cumulative food intake, food efficiency, respiratory exchange ratio and a decrease of energy expenditure. Co-administration of the ghrelin receptor antagonist JMV2959 suppressed/blocked the majority of these effects, with the notable exception of ghrelin-induced food intake and food efficiency. The hypothesis emerging from these data, namely that GHS-R1A mediates the chronic effects of ghrelin on fat accumulation, at least partly independent of food intake, is discussed in light of the accompanying data regarding the hypothalamic genes coding for peptides and receptors involved in energy balance regulation, which were found to have altered expression in these studies.
Full-text Article · Oct 2009 · Journal of Neuroendocrinology
[Show abstract][Hide abstract]ABSTRACT: The stomach-derived hormone ghrelin interacts with key CNS circuits regulating energy balance and body weight. Here we provide evidence that the central ghrelin signaling system is required for alcohol reward. Central ghrelin administration (to brain ventricles or to tegmental areas involved in reward) increased alcohol intake in a 2-bottle (alcohol/water) free choice limited access paradigm in mice. By contrast, central or peripheral administration of ghrelin receptor (GHS-R1A) antagonists suppressed alcohol intake in this model. Alcohol-induced locomotor stimulation, accumbal dopamine release and conditioned place preference were abolished in models of suppressed central ghrelin signaling: GHS-R1A knockout mice and mice treated with 2 different GHS-R1A antagonists. Thus, central ghrelin signaling, via GHS-R1A, not only stimulates the reward system, but is also required for stimulation of that system by alcohol. Our data suggest that central ghrelin signaling constitutes a potential target for treatment of alcohol-related disorders.
Full-text Article · Jul 2009 · Proceedings of the National Academy of Sciences
[Show abstract][Hide abstract]ABSTRACT: Here we provide the first pharmacological exploration of the impact of acute central nervous system exposure to three recently developed ghrelin receptor (GHS-R1A) ligands on food intake and on the electrical activity of the target cells for ghrelin in the hypothalamus. Central (i.c.v) injection of GHS-R1A antagonists to rats suppressed food intake induced by i.c.v ghrelin injection (1 microg) in a dose-dependent manner with a total blockade at concentrations of 0.4 microg and 8 microg for JMV 3002 and JMV 2959 respectively. JMV 2810, a partial agonist, also suppressed ghrelin-induced food intake (range: 0.02-2 microg). Moreover all three compounds reduced fasting-induced food intake in rats (i.e. the amount of food eaten during the first hour of food exposure after a 16 h fast). At the single cell level we also explored the effects of the compounds to suppress ghrelin (0.5 microM)-induced changes in electrical activity of arcuate nucleus cells recorded extracellularly in a slice preparation. Preincubation followed by perfusion with the GHS-R1A ligands suppressed the responsiveness of arcuate cells to ghrelin. Thus, the recently developed GHS-R1A ligands (JMV 3002, 2959 and 2810) suppress ghrelin-induced and fasting-induced food intake at the level of the central nervous system. This appears to be mediated, at least in part, by a modulation of the activity of ghrelin-responsive arcuate nucleus cells. As the central ghrelin signalling system has emerged as an important pro-obesity target, it will be important to establish the efficacy of these GHS-R1A ligands to reduce fat mass in clinical studies.
Full-text Article · May 2009 · European journal of pharmacology
[Show abstract][Hide abstract]ABSTRACT: Energy homeostasis is controlled by a complex regulatory system of molecules that affect food intake and that are critical for maintaining a stable body weight during life. Ghrelin is a peptide of 28 amino acid synthesized predominantly by the stomach and the gut, which activate the type 1a growth hormone (GH) secretagogue receptor (GHS-R1a), a G-protein coupled receptor. The acylated form of ghrelin potently stimulates GH secretion both in vitro and in vivo in several animal species, including humans. Beside the endocrine effect, ghrelin shows also extraendocrine activities, including stimulation of feeding behaviour. Several classes of small synthetic peptide and non-peptide ligands of the GHS-R1a have been described and are able to release GH and stimulate food intake. However, in time, it appeared that the stimulating effects on GH secretion could be divorced from those on food intake, suggesting that more than a single receptor might be involved. Several experimental data have even questioned the physiological role of ghrelin in the control of GH secretion and energy metabolism. By using novel agonists, partial agonists, and antagonists for the GHS-R1a receptor, we have studied whether the stimulation of this receptor could account for the purported physiological role of ghrelin. Our results demonstrate that the ability to bind in vitro the GHS-R1a is not predictive of the in vivo biological activity of the compounds and that the endocrine and extraendocrine effects could be mediated also by receptors different from the GHS-R1a.
Article · Oct 2008 · Eating and weight disorders: EWD
[Show abstract][Hide abstract]ABSTRACT: Ghrelin receptor ligands based on trisubstituted 1,2,4-triazole structure were synthesized and evaluated for their in vitro binding and biological activity. In this study, we explored the replacement of the alpha-aminoisobutyryl moiety by aromatic or heteroaromatic groups. Compounds 5 and 34 acted as potent in vivo antagonists of hexarelin-stimulated food intake. These two compounds did not stimulate growth hormone secretion in rodents and did not antagonize growth hormone secretion induced by hexarelin.
Article · Mar 2008 · Journal of Medicinal Chemistry
[Show abstract][Hide abstract]ABSTRACT: A series of ghrelin receptor ligands based on the trisubstituted 1,2,4-triazole structure were synthesized and evaluated for their in vitro binding and biological activity. In this study, we explored the significance of the aminoisobutyryl (Aib) moiety, a common feature in numerous growth hormone secretagogues described in the literature. Potent agonist and antagonist ligands of the growth hormone secretagogue receptor type 1a (GHS-R1a) were obtained, i.e., compounds 41 (JMV2894) and 17 (JMV3031). The best compounds were evaluated for their in vivo activity on food intake, after sc injection in rodents. Among the tested compounds, few of them were able to stimulate food intake and some others, i.e., compounds 4 (JMV2959), 17, and 52 (JMV3021), acted as potent in vivo antagonist of hexarelin-stimulated food intake. These compounds did not stimulate growth hormone secretion in rats and furthermore did not antagonize growth hormone secretion induced by hexarelin, revealing that it is possible to modulate food intake without altering growth hormone secretion.
Full-text Article · Dec 2007 · Journal of Medicinal Chemistry
[Show abstract][Hide abstract]ABSTRACT: A new series of growth hormone secretagogue (GHS) analogues based on the 1,2,4-triazole structure were synthesized and evaluated for their in vitro binding and their ability to stimulate intracellular calcium release to the cloned hGHS-1a ghrelin receptor expressed in LLC PK-1 cells. We have synthesized potent ligands of this receptor, some of them behaving as agonists, partial agonists, or antagonists. Some compounds among the most potent, i.e., agonist 29c (JMV2873), partial agonists including 21b (JMV2810), antagonists 19b (JMV2866) and 19c (JMV2844), were evaluated for their in vivo activity on food intake, after sc injection in rodents. Some compounds were found to stimulate food intake like hexarelin; some others were identified as potent hexarelin antagonists in this assay. Among the tested compounds, 21b was identified as an in vitro ghrelin receptor partial agonist, as well as a potent in vivo antagonist of hexarelin-stimulated food intake in rodents. Compound 21b was without effect on GH release from rat. However, in this series of compounds, it was not possible to find a clear correlation between in vitro and in vivo results.
Article · May 2007 · Journal of Medicinal Chemistry