Development of Nonpeptidic Inverse Agonists of the Ghrelin Receptor (GHSR) Based on the 1,2,4-Triazole Scaffold

GHSR controls, among others, growth
hormone and insulin secretion,
adiposity, feeding, and glucose metabolism. Therefore, an inverse
agonist ligand capable of selectively targeting GHSR and reducing
its high constitutive activity appears to be a good candidate for
the treatment of obesity-related metabolic diseases. In this context,
we present a study that led to the development of several highly potent
and selective inverse agonists of GHSR based on the 1,2,4-triazole
scaffold. We demonstrate that, depending on the nature of the substituents
on positions 3, 4, and 5, this scaffold leads to ligands that exert
an intrinsic inverse agonist activity on GHSR-catalyzed G protein
activation through the stabilization of a specific inactive receptor
conformation. Thanks to an in vivo evaluation, we also show that one
of the most promising ligands not only exerts an effect on insulin
secretion in rat pancreatic islets but also affects the orexigenic
effects of ghrelin in mice.