Design and characterization of a triazole-based growth hormone secretagogue receptor modulator inhibiting the glucoregulatory and feeding actions of ghrelin.

Autor: Péraldi-Roux S; IBMM, Univ Montpellier, CNRS, ENSCM, Montpellier, France., Bayle M; IBMM, Univ Montpellier, CNRS, ENSCM, Montpellier, France., M'Kadmi C; IBMM, Univ Montpellier, CNRS, ENSCM, Montpellier, France., Damian M; IBMM, Univ Montpellier, CNRS, ENSCM, Montpellier, France., Vaillé J; IBMM, Univ Montpellier, CNRS, ENSCM, Montpellier, France., Fernandez G; Laboratory of Neurophysiology of the Multidisciplinary Institute of Cell Biology (IMBICE) -Argentine Research Council (CONICET), Scientific Research Commission, Province of Buenos Aires (CIC-PBA), National University of La Plata, La Plata, Buenos Aires, Argentina., Cornejo MP; Laboratory of Neurophysiology of the Multidisciplinary Institute of Cell Biology (IMBICE) -Argentine Research Council (CONICET), Scientific Research Commission, Province of Buenos Aires (CIC-PBA), National University of La Plata, La Plata, Buenos Aires, Argentina., Marie J; IBMM, Univ Montpellier, CNRS, ENSCM, Montpellier, France., Banères JL; IBMM, Univ Montpellier, CNRS, ENSCM, Montpellier, France., Ben Haj Salah K; IBMM, Univ Montpellier, CNRS, ENSCM, Montpellier, France., Fehrentz JA; IBMM, Univ Montpellier, CNRS, ENSCM, Montpellier, France., Cantel S; IBMM, Univ Montpellier, CNRS, ENSCM, Montpellier, France., Perello M; Laboratory of Neurophysiology of the Multidisciplinary Institute of Cell Biology (IMBICE) -Argentine Research Council (CONICET), Scientific Research Commission, Province of Buenos Aires (CIC-PBA), National University of La Plata, La Plata, Buenos Aires, Argentina; Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, Uppsala, Sweden., Denoyelle S; IBMM, Univ Montpellier, CNRS, ENSCM, Montpellier, France., Oiry C; IBMM, Univ Montpellier, CNRS, ENSCM, Montpellier, France. Electronic address: catherine.oiry-cuq@umontpellier.fr., Neasta J; IBMM, Univ Montpellier, CNRS, ENSCM, Montpellier, France. Electronic address: jeremie.neasta@umontpellier.fr.
Jazyk: angličtina
Zdroj: Biochemical pharmacology [Biochem Pharmacol] 2022 Aug; Vol. 202, pp. 115114. Date of Electronic Publication: 2022 May 31.
DOI: 10.1016/j.bcp.2022.115114
Abstrakt: The growth hormone secretagogue receptor (GHSR) is a G protein-coupled receptor that regulates essential physiological functions. In particular, activation of GHSR in response to its endogenous agonist ghrelin promotes food intake and blood glucose increase. Therefore, compounds aimed at blocking GHSR signaling constitute potential options against obesity-related metabolic disorders. We have previously developed potent ligands of GHSR based on a triazole scaffold. Here, we report a new 3,4,5-trisubstituted 1,2,4-triazole compound, named JMV 6616, that potently blocks GHSR activity in vitro and in vivo. Specifically, in HEK293T cells JMV 6616 behaves as an inverse agonist since it binds to GHSR and inhibits its ghrelin-independent signaling. Accordingly, using purified labeled GHSR assembled into lipid nanodiscs we found that JMV 6616 decreases GHSR-catalyzed G protein activation and stabilizes an inactive receptor conformation. Importantly, JMV 6616 also acts on native GHSR since it blocks the insulinostatic effect of ghrelin in pancreatic islets. In mice, JMV 6616 inhibits blood glucose-raising effects of ghrelin treatment and the orexigenic actions of acute ghrelin administration. Together, our data suggest that this triazole-derived modulator of GHSR holds promise to mitigate several pathological features associated with eating and metabolic disorders.
(Copyright © 2022 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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