1. Development of non-peptidic inverse agonists of the ghrelin receptor (GHSR) based on the 1,2,4-triazole scaffold
- Author
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Sonia Cantel, Jean-Alain Fehrentz, Severine Denoyelle, Catherine Oiry, Gimena Fernandez, Mario Perello, Sylvie Peraldi-Roux, Jean-Louis Banères, Céline M'Kadmi, Guadalupe García Romero, Jacky Marie, Sophie Mary, Mathieu Maingot, Marjorie Damian, Anne-Laure Blayo, Jérémie Neasta, Khoubaib Ben Haj Salah, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Instituto Multidisciplinario de Biología Celular [La Plata] (IMBICE), Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET)-Comisión de Investigaciones Científicas [Buenos Aires] (CIC)-Universidad Nacional de la Plata [Argentine] (UNLP), and Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
medicine.medical_specialty ,Scaffold ,Drug Inverse Agonism ,[CHIM.THER]Chemical Sciences/Medicinal Chemistry ,Carbohydrate metabolism ,Ligands ,Growth hormone ,01 natural sciences ,Islets of Langerhans ,03 medical and health sciences ,chemistry.chemical_compound ,GTP-Binding Proteins ,Internal medicine ,Insulin Secretion ,Drug Discovery ,medicine ,Animals ,Humans ,Inverse agonist ,[CHIM]Chemical Sciences ,Receptors, Ghrelin ,Receptor ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,0303 health sciences ,010405 organic chemistry ,digestive, oral, and skin physiology ,1,2,4-Triazole ,Triazoles ,Ligand (biochemistry) ,Rats ,0104 chemical sciences ,HEK293 Cells ,Endocrinology ,chemistry ,Molecular Medicine ,Ghrelin - Abstract
International audience; 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, 2 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.
- Published
- 2020