Endocrine PharmacologyAnorexigenic and electrophysiological actions of novel ghrelin receptor (GHS-R1A) antagonists in rats
Introduction
The central ghrelin signalling system continues to receive considerable interest as a potential therapeutic target for the regulation of appetite and fat mass (for review see e.g. Vincent and le Roux, 2007). Indeed, a number of studies have shown that suppressed ghrelin signalling has beneficial effects to prevent/reverse obesity in animal studies (Asakawa et al., 2003, Esler et al., 2007). To this end, a number of so-called ghrelin receptor ligands (antagonists, partial agonists and inverse agonists) have been developed that include a recently described group of non-peptides possessing a trisubstituted 1,2,4-triazole structure (Demange et al., 2007, Moulin et al., 2007, Moulin et al., 2008).
Ghrelin was discovered by Kojima et al. (1999), who identified it as the first endogenous ligand for the cloned growth hormone secretagogue receptor (GHS-R1A). The stomach appears to be the main source of circulating ghrelin as gastrectomy surgery depletes circulating ghrelin by 60–85% in rodents (Dornonville de la Cour et al., 2005). Treatment with ghrelin and synthetic mimetics (the growth hormone secretagogues) has been shown to increase food intake in both rodents (Locke et al., 1995) and humans (Wren et al., 2001) and to increase fat mass in rodents (Lall et al., 2001, Tschöp et al., 2000).
In man, there is an inverse relationship between circulating ghrelin levels and fat mass (Tschöp et al., 2001) suggesting that obesity is not caused by hyperghrelinaemia. Taken together with the modest energy balance phenotype in mice lacking ghrelin or GHS-R1A (Sun et al., 2003, Wortley et al., 2005, Zigman et al., 2005) these findings raise questions as to whether antagonism of the ghrelin signalling system would provide an effective anti-obesity therapy. However, there is good reason for optimism as modest changes in ghrelin sensitivity would be expected to suppress the sensation of hunger. This is implied in the elegant studies of Cummings et al. (2004) in which the amount of hunger reported by subjects devoid of meal cues was directly related to the blood ghrelin levels. Also, the postprandial decrease in ghrelin was less pronounced in obese (le Roux et al., 2005) as well as binge eating subjects (Kojima et al., 2005). Thus, suppressed ghrelin signalling, for example, by antagonism of GHS-R1A, may provide an effective therapy to reduce hunger provided that the compound is able to access the central ghrelin signalling system. Such a compound may need to gain access to the hypothalamus, where the primary target neurones appear to be the orexigenic neuropeptide Y/agouti-related peptide (Dickson and Luckman, 1997) but also to higher central nervous system sites that include circuits involved in reward-seeking behaviour, eg the mesolimbic dopaminergic system (Jerlhag et al., 2006, Jerlhag et al., 2007).
The aims of the present study are (1) to determine whether novel ghrelin receptor ligands, two antagonists and one partial agonist, are able to suppress centrally the acute effects of ghrelin on food intake and (2) to determine whether such effects are exerted at the single cell level, within the established hypothalamic circuits through which ghrelin acts.
Section snippets
Synthesis and pharmacological profiling of GHS-R1A ligands
The GHS-R1A ligands used in the present study are novel triazole derivatives synthesized at the Institut des Biomolécules Max Mousseron (IBMM) of the Montpellier 1 and 2 University. The chemical nomenclature of the compounds are JMV 2959: (R)-N-(1-(4-(4-Methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-aminoacetamide; JMV 2810: (R)-N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide; JMV
In vitro pharmacological characterization of tested GHS-R1A ligands
Table 1 shows the binding affinity to and action profile on GHS-R1A for the three compounds used in the present study. JMV 3002 had the better affinity with an IC50 at 1.1 nM. JMV 2959 and JMV 2810 displayed a similar affinity (32 ± 3 nM vs 33 ± 7 nM respectively). Their ability to activate the GHS-R1A and to stimulate a biological response was determined by assessing the increase in intracellular calcium levels. While JMV 3002 and JMV 2959 did not activate calcium mobilisation and behave as
Discussion
We show for the first time that the recently developed ghrelin receptor ligands, two competitive antagonists (JMV 3002 and JMV 2959) and one partial agonist (JMV 2810), act centrally to block food intake in physiological (fasting) and pharmacological models of elevated ghrelin signalling. We also provide electrophysiological data showing that the central effects of the GHS-R1A antagonists include a suppression of ghrelin-induced changes in firing rate in a sub-population of arcuate nucleus
Acknowledgments
This research was supported by the Swedish Medical Research Council (VR k2007-54x-20328-013), European Commission 6th Framework (EC LSHM-CT-2003-503041), Novo Nordisk Fonden (GeA/AIR), ALF Göteborg (SU7601) and the Swedish Foundation for Strategic Research to Sahlgrenska Center for Cardiovascular and Metabolic Research (A305-188).
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The authors have contributed equally to the work.