Toward Potent Ghrelin Receptor Ligands Based on Trisubstituted 1,2,4-Triazole Structure. 2. Synthesis and Pharmacological in Vitro and in Vivo Evaluations

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.

Agonism, Antagonism, and Inverse Agonism Bias at the Ghrelin Receptor Signaling

“…In this particular situation, detection of partial agonists was problematic because the high basal level of IP1 production might hide the partial agonist character of some ligands. This was the case for JMV 2959, first reported as an antagonist (35,47), but it displayed no or partial agonist activity depending on whether the basal activity was higher or lower than 60% of the maximal ghrelin response. Indeed, we unambiguously highlighted here the partial agonist character of JMV 2959 and of other compounds (JMV 3002 and JMV 3018) by testing their efficacy on the GHS-R1a-A204E mutant, which exhibits a low constitutive activity (42).…”

“…Materials and Methods-Ghrelin (35), and JMV 3002, JMV 3018, and JMV 3011 were described previously by Moulin et al (36). In compound JMV 4484, a second chiral center was introduced at position 3 of the 1,2,4-triazole scaffold.…”

“…It also remains to be assessed whether the ligand-directed functional selectivity toward downstream signaling pathways leads to a functional selectivity toward physiological functions controlled by the ghrelin/GHS-R1a axis. One can nevertheless point out that in vivo studies in rat demonstrated that JMV 2959 inhibited food intake and addiction but not GH secretion promoted by ghrelin (35,47). This observation is of importance because it suggests that a potential link may exist between the selective action of JMV 2959 toward the signaling pathways activated by GHS-R1a and its selective antagonist action toward physiological responses promoted by ghrelin (Fig.…”

Requirement of central ghrelin signaling for alcohol reward

“…Validation using 2 different GHS-R1A antagonists in these models was important because of their different pharmacological profile with respect to food intake. Whereas JMV2959 suppresses food intake by a GHS-R1A agonist (hexarelin) as expected (24,30), BIM28163 paradoxically stimulates food intake (23) via an unknown mechanism that is likely to be independent of GHS-R1A and also independent of ghrelin signaling at the level of the mesolimbic dopaminergic system. Our demonstration that both GHS-R1A antagonists block alcohol intake in a free-choice limited access paradigm together with the absence of ghrelin-induced alcohol consumption in GHS-R1A knockout mice suggests that endogenous ghrelin signaling via GHS-R1A is required for the rewarding properties of alcohol.…”

The effect of the ghrelin receptors inhibitor [D-Lys3]-GHRP-6 on the levels and metabolism of monoamines in symmetric brain areas of rats treated chronically with alcohol

“…Имеются данные об участии грелиновой системы в формировании алкогольной зависимости. Так, введение грелина повышает [12], а блокада грелиновых рецепторов снижает [12,13,16] потребление алкоголя мышами. Предполагается, что эти функции либо опосредова-ны моноаминергической регуляцией, либо реализу-ются через гетеродимерный рецептор GHSR1a/D1R [14,23].…”