Résumé
The GHSR was initially identified as the growth hormone secretagogue receptor. In addition to its ability to stimulate growth hormone secretion, this G protein-coupled receptor is also involved in the regulation of several essential physiological functions. In particular, activation of GHSR in response to its endogenous agonist peptide ligand ghrelin stimulates food intake, controls adiposity and promotes blood glucose increase. Interestingly, this receptor possesses a very high constitutive activity presumed to induce constant appetite and to trigger food intake between meals. Therefore, inverse agonist compounds capable of selectively targeting the GHSR, reducing its constitutive activity and inhibiting selective physiological effects induced by ghrelin, appear to be promising candidates for the treatment of obesity-related metabolic disorders. In this context, we developed several highly potent and selective inverse agonists of GHSR based on the 1,2,4-triazole derivative JMV2959, a peptidomimetic compound capable of both inhibiting agonist- or fasting-induced food intake and reducing the accumulation of fat mass without preventing the secretion of growth hormone. We demonstrated that, depending on the chemical modulation of the substituents, this scaffold led 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 in vivo studies in mice, we also showed that promising ligands attenuate several pathological features associated with obesity-related disorders including ghrelin-induced blood glucose raise and food intake.